KR0163586B1 - Substituted quinazolinones as angiotensin-ii antagonists - Google Patents

Abstract

Novel substituted quinazolinones of the formula (I), which are useful as angiotension II antagonists, are disclosed. <CHEM>

Description

[Name of invention]

Substituted Quinazolinones as Angiotensin II Antagonists

Detailed description of the invention

The present invention relates to novel substituted quinazolinone compounds and derivatives thereof useful as angiotensin II antagonists in the treatment of elevated blood pressure and congestive heart failure. Thus, the substituted quinazolinone compounds of the present invention are useful as antihypertensive agents.

The Lenin-Angiotensin System (RAS) plays a central role in the regulation of normal blood pressure and is believed to be critically involved in congestive heart failure as well as the development and maintenance of hypertension. Angiotensin II (AII), or otapeptide hormone, is produced primarily in the blood during the degradation of angiotensin I by angiotensin converting enzyme (ACE), which is located on the vascular endothelium of lungs, kidneys and many other tissues and is the final product of RAS. . AII is a potent arterial vasoconstrictor that works by interacting with specific receptors present in the cell membrane. One aspect of controlling RAS is angiotensin II receptor antagonism. Several peptide analogs of AII are known to inhibit the effects of this hormone by competitively blocking receptors, but experimental and clinical applications have been limited due to the lack of partial agonist activity and oral absorption. M. Antonaccio . Clin. Exp. Hypertens. A4. 27-46 (1982): D. H. P. Streeten and G. H. Anderson. Jr.- Handbook of Hypertension, Clinical Pharmacology of Antihypertensive Drugs. ed. A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher. Amsterdam. The Netherlands, 1984].

Recently, several non-peptide compounds have been described as AII antagonists. Such compounds are disclosed in U.S. Pat.Nos. 4,207,324, 4,340,598, 4,576,958, 4,582,847 and 4,880,804, EP 028,834, 245,637, 253,310 and 291,969, and literature references. , et al., Eur. J. Pharm. Exp. Therap. 157, 13-21 (1988) and P. C. Wong, et al. Pharm. Exp. Therap. 247, 1-7, Hypertension, 13, 489-497 (1988)]. All US patents, EP 028,834 and 253,310 and both documents describe substituted imidazole compounds, which are usually linked to substituted phenyl via lower alkylbridges. EP 245,637 describes derivatives of 4,5,6,7-tetrahydro-2H-imidazo [4,5-c] pyridine-6-carboxylic acid and analogues thereof as antihypertensive agents.

The present invention relates to novel substituted quinazolinone compounds and derivatives thereof useful as angiotensin II antagonists and antihypertensive agents useful for treating congestive heart failure and high intraocular pressure. Compounds of the present invention are compounds of formula (I) and pharmaceutically acceptable salts thereof.

In general formula (I) above,

L is linked to J or K to form an aromatic ring as defined below,

J is -C (= M)-or J and L are linked together to form an aromatic ring of 6 carbon atoms substituted with R ^7a , R ^7b , R ^8a and R ^8b , provided that only one of J and K is -C (= M)-,

K is -C (= M) ^-or K and L are linked together to form an aromatic aromatic group of 6 carbon atoms substituted with R ^a7 , R ^7b , and R ^8a and R ^8b , provided that only one of J and K is -C ( = M)-,

M is oxygen or NR ²² ,

R ¹ is (a) —CO ₂ R ⁴ ,

(b) -SO ₃ R ⁵ ,

(c) -NHSO ₂ CF ₃ ,

(d) -PO (OR ⁵ ) ₂ ,

(e) -SO ₂ -NH-R ⁹ ,

(f) -CONHOR ⁵ ,

(i) -SO ₂ NH-heteroaryl as defined below,

(j) -CH ₂ SO ₂ NH-heteroaryl as defined below,

(k) -SO ₂ NH-CO-R ²³ ,

(l) -CH ₂ SO ₂ NH-CO-R ²³ ,

(m) -CONH-SO ₂ R ²³ ,

(n) -CH ₂ CONH-SO ₂ R ²³ ,

(o) -NHSO ₂ NHCO-R ²³ ,

(p) -NHCONHSO ₂ -R ²³ ,

(t) -CONHNHSO ₂ CF ₃ ,

(u) -SO ₂ NH-CN,

(x) -PO (OR ⁵ ) (OR ⁴ ) or

(y) —SO ₂ NHCONR ⁴ R ²³ wherein heteroaryl is an unsubstituted, mono- or disubstituted five-membered which may optionally contain one to three heteroatoms selected from the group consisting of O, N and S or 6-membered aromatic ring, wherein the substituents are -OH, -SH, -C ₁ -C ₄ -alkyl, -C ₁ -C ₄ -alkoxy, -CF ₃ , halo (Cl, Br, F, I), -NO ₂ , -CO ₂ H, -CO _2- (C ₁ -C ₄ -alkyl), -NH ₂ , -NH (C ₁ -C ₄ -alkyl) and -N (C ₁ -C ₄ -alkyl) ₂ Is selected from the group consisting of

R ^2a and R ^2b are each independently

(a) H,

(b) halogen (Cl, Br, I, F),

(c) NO _2,

(d) NH _2,

(e) C ₁ -C ₄ -alkylamino,

(f) di (C ₁ -C ₄ -alkyl) amino,

(g) SO ₂ NHR ⁹ ,

(h) CF _3,

(i) C ₁ -C ₄ -alkyl,

(j) C ₁ -C ₆ -alkoxy,

(k) C ₁ -C ₆ -alkyl-S-,

(l) C ₂ -C ₆ -alkenyl,

(m) C ₂ -C ₆ -alkynyl,

(n) aryl as defined below,

(o) aryl (C ₁ -C ₄ -alkyl) or

(p) C ₃ -C ₇ -cycloalkyl,

R ^3a is

(a) H,

(b) halo (Cl, Br, I, F),

(c) C ₁ -C ₆ -alkyl,

(d) C ₁ -C ₆ -alkoxy or

(e) C ₁ -C ₆ -alkoxyalkyl,

R ^3b is

(a) H,

(b) halo (Cl, Br, I, F),

(c) NO _2,

(d) C ₁ -C ₆ -alkyl,

(e) C ₁ -C ₆ -acyloxy,

(f) C ₃ -C ₇ -cycloalkyl,

(g) C ₁ -C ₆ -alkoxy,

(h) -NHSO ₂ R ⁴ ,

(i) hydroxy (C ₁ -C ₄ -alkyl),

(j) aryl (C ₁ -C ₄ -alkyl),

(k) C ₁ -C ₄ -alkylthio,

(l) C ₁ -C ₄ -alkyl sulfinyl,

(m) C ₁ -C ₄ -alkyl sulfonyl,

(n) NH _2,

(o) C ₁ -C ₄ -alkylamino,

(p) di (C ₁ -C ₄ -alkyl) amino,

(q) fluoro-C ₁ -C ₄ -alkyl-,

(r) -S0 ₂ -NHR ⁹ ,

(s) aryl as defined below,

(t) furyl,

(u) CF ₃ ,

(v) C ₂ -C ₆ -alkenyl or

(w) C ₂ -C ₆ -alkenyl, wherein aryl is halo (Cl, Br, I, F), N (R ⁴ ) ₂ , CO ₂ R ⁴ , C ₁ -C ₄ -alkyl, C _1- C ₄ -alkoxy, NO ₂ , CF ₃ , C ₁ -C ₄ -alkylthio, and phenyl or naphthyl optionally substituted with one or two substituents selected from the group consisting of OH,

R ⁴ is H, aryl as defined above, or straight or branched C ₁ -C ₆ -alkyl optionally substituted with aryl as defined above,

R ^4a is aryl as defined above or is straight or branched C ₁ -C ₆ -alkyl optionally substituted with aryl as defined above,

E is a single bond, -NH ¹³ (CH ₂ ) _S- , S (O) _X (CH ₂ ) _S- (where _X is 0 to 2 and _S is 0 to 5), -CH (OH)- , -O- or CO-,

R ⁶ is (a) halo (Cl, Br, I, F), -OC ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl, -NO ₂ , -CF ₃ , -SO ₂ NR ⁹ R ¹⁰ , Aryl as defined above optionally substituted with one or two substituents selected from the group consisting of -SC ₁ -C ₄ -alkyl, -OH, -NH ₂ , C ₃ -C ₇ -cycloalkyl, and C ₃ -C ₁₀ -alkenyl ,

(b) aryl as defined above, C ₃ -C ₇ -cycloalkyl, halo (Cl, Br, I, F), CF ₃ , CF ₂ CF _3, -NH ₂ , -NH (C ₁ -C ₄ -alkyl ), -OR ⁴ -N (C ₁ -C ₄ -alkyl) ₂ , -NH-SO ₂ R ⁴ , -COOR ⁴ and SO ₂ NHR ⁹ straight or branched chain C optionally substituted with a substituent selected from the group consisting of ₁ -C ₆ -alkyl, C ₂ -C ₅ -alkenyl or C ₂ -C ₅ -alkynyl,

(c) an unsubstituted, mono- or di-substituted heteroaromatic 5 or 6-membered cyclic ring which may contain one or two elements selected from the group consisting of N, O and S, wherein the substituent is -OH, Is selected from the group consisting of -SH, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, -CF ₃ , halo (Cl, Br, I, F) and NO ₂ ],

(d) C ₃ -C ₇ -cycloalkyl,

(e) perfluoro-C ₁ -C ₄ -alkyl or

(f) H,

R ^7a and R ^7b are independently

(a) H,

(b) straight or branched C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl,

(c) halo (Cl, Br, I, F) or _,

(d) CF _3, or

(e) when R ^7a and R ^7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring,

R ^8a and R ^8b are independently

(a) H,

(b) -OH,-guanidino, C ₁ -C ₄ -alkoxy, -N (R ⁴ ) ₂ , COOR ⁴ , -CON (R ⁴ ) ₂ , -O-COR ⁴ , -aryl, -heteroaryl , -S (O) xR ²³ , -tetrazol-5-yl, -CONHSO ₂ R ²³ , -SO ₂ NH-heteroaryl, -SO ₂ NHCOR ²³ , -PO (OR ⁴ ) ₂ , -PO (OR ⁴ C ₁ -C ₆ -alkyl optionally substituted with a substituent selected from the group consisting of R ⁹ , -SO ₂ NH-CN, and -NR ¹⁰ COOR ²³ ,

(c) -CO-aryl,

(d) -C ₃ -C ₇ -cycloalkyl,

(e) halo (Cl, Br, I, F),

(f) -OH.

(g) -0R ²³ ,

(h) -C ₁ -C ₄ -perfluoroalkyl,

(i) -S (O) xR ²³ ,

(j) -COOR ⁴ ,

(k) -SO ₂ H,

(l) -NR ⁴ R ²³ ,

(m) -NR ⁴ COR ²³ ,

(n) -NR ⁴ COR ²³ ,

(o) -SO ₂ NR ⁹ R ¹⁰ ,

(p) -NO ₂ ,

(q) -N (R ⁴ ) SO ₂ R ²³ ,

(r) -NR ⁴ CONR ⁴ R ²³ ,

(t) -aryl or -heteroaryl as defined above,

(u) -NHSO ₂ CF ₃ ,

(v) -SO ₂ NH-heteroaryl,

(w) -SO ₂ NHCOR ²³ ,

(x) -CONHSO ₂ R ²³ ,

(y) -PO (OR ⁴ ) ₂ ,

(z) -PO (OR ⁴ ) R ⁹ ,

(aa) -tetrazol-5-yl,

(bb) -CONH (tetrazol-5-yl)

(cc) -COR ⁴ ,

(dd) -SO ² NHCN or

(여기서, n은 O 또는 1이다)이고,(ee)

(Where n is O or 1),

R ⁹ is H, C ₁ -C ₅ -alkyl, aryl or arylmethyl,

R ¹⁰ is H or C ₁ -C ₄ -alkyl,

(여기서, R²⁰은 H, -NO₂, -NH₂, -OH 또는 -OCH₃이다)이고,R ¹¹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkoxyalkyl or

Wherein R ²⁰ is H, —NO ₂ , —NH ₂ , —OH, or —OCH ₃ , and

R ¹² is —CN, —NO ₂ or —CO ₂ R ⁴ ,

R ¹³ is H, (C ₁ -C ₄ -alkyl) CO-, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, aryl or arylmethyl,

R ¹⁴ is H, C ₁ -C ₈ -alkyl, C ₁ -C ₈ -perfluoroalkyl, C ₃ -C ₆ -cycloalkyl, aryl or arylmethyl,

R ¹⁵ is H or C ₁ -C ₆ -alkyl,

R ¹⁶ is H, C ₁ -C ₆ -alkyl, C ₃ -C ₆ cycloalkyl, aryl or arylmethyl,

또는

이고,R ¹⁷ is -NR ⁹ R ¹⁰ , -OR ¹⁰ , -NHCONH ₂ , -NHCSNH ₂ ,

or

ego,

R ¹⁸ and R ¹⁹ are each independently C ₁ -C ₄ -alkyl, or together they form — (CH ₂ ) q— where q is 2 or 3, and

R ²⁰ is H, —NO _2, —NH _2, —CH or OCH ₃ ,

R ²¹ is H, aryl, or aryl, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , -CO ₂ R ⁴ , -OH, SO ₃ C ₁ -C ₄ -alkyl optionally substituted with H or SO ₂ NH ₂ ,

R ²² is a) heteroaryl as defined above or

b) heteroaryl as defined above or

c) aryl as defined above, heteroaryl as defined above, -OH, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , CO ₂ R ⁴ , halo ( C ₁ -C ₄ -alkyl optionally substituted with a substituent selected from the group consisting of Cl, Br, F, I) and -CF ₂ ,

R ²³ is a) heteroaryl as defined above,

b) heteroaryl as defined above,

c) C ₃ -C ₇ -cycloalkyl,

d) aryl as defined above, heteroaryl as defined above, -OH, -SH, C ₁ -C ₄ -alkyl, -O (C ₁ -C ₄ -alkyl), -S (C ₁ -C ₄ -alkyl),- CF _3, halo (Cl, Br, F, I), -NO _2, CO ₂ H, CO ₂ -C ₁ -C ₄ -alkyl, -NH ₂ , -NH (C ₁ -C ₄ -alkyl),- Optionally substituted with a substituent selected from the group consisting of N (C ₁ -C ₄ -alkyl) ₂ , -PO ₃ H ₂ , -PO (OH) (OC ₁ -C ₄ -alkyl) and -PO (OR ⁴ ) R ⁹ C ₁ -C ₆ -alkyl or

e) perfluoro-C ₁ -C ₄ -alkyl,

X is a) a carbon-carbon single bond,

b) -CO-,

c) -O-,

d) -S-,

h) -OCH _2- ,

I) -CH ₂ O-,

j) -SCH _2- ,

k) -CH ₂ S-,

l) -NHC (R ⁹ ) (R ¹⁰ ),

m) -NR ⁹ SO _2- ,

n) -SO ₂ NR ^9- ,

o) -C (R ⁹ ) (R ¹⁰ ) NH-,

p) -CH = CH-,

q) -CF = CF-,

r) -CH = DF-,

s) -CF = CH-,

t) -CH ₂ CH _2- ,

u) -CF ₂ CF _2- ,

r is 1 or 2.

One embodiment of the compound of formula (I)

J is -C (O)-,

K and L combine together to form an aromatic ring of 6 carbon atoms substituted with R ^7a , R ^7b , R ^8a and R ^8b ,

R ¹ is

(a) -COOH,

(c) -NH-SO ₂ CF ₂ ,

(d) -SO ₂ NH-heteroaryl as defined above

(e) -CH ₂ -SO ₂ NH-heteroaryl as defined above

(f) -SO ₂ NH-CO-R ²³ ,

(g) -CH ₂ SO ₂ NH-CO-R ²³ ,

(h) -CONH-SO ₂ R ²³ ,

(i) -CH ₂ CONH-SO ₂ R ²³ ,

(j) -NHSO ₂ NHCO-R ²³ or

(k) -NHCONHSO ² -R ²³ ,

R ^2a is H,

R ^2b is H, fluorine, chlorine, CF ₃ , C ₁ -C ₆ -alkyl, C ₂ -C ₄ -alkenyl, or C ₂ -C ₄ -alkynyl,

R ^3a is H,

R ^3b is H, fluorine, chlorine, CF ₃ , C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, or C ₂ -C ₄ -alkynyl, C ₅ -C ₆ -cycloalkyl, -COOCH ₃ , -COOC ₂ H ₅ , -SO ₂ -CH ₃ , NH ₂ , -N (C ₁ -C ₄ -alkyl) ₂ or -NH-SO ₂ CH ₃ ,

E is a single bond, -O- or -S-,

R ⁶ is

a) from the group consisting of C ₃ -C ₅ -cycloalkyl, chlorine, CF ₃ , -CCI ₃ , -O-CH ₃ , OC ₂ H ₅ , -S-CH ₃ , -SC ₂ H ₅ , phenyl and fluorine C ₁ -C ₅ -alkyl optionally substituted with selected substituents,

b) C ₂ -C ₅ -alkenyl or C ₂ -C ₅ -alkynyl or

c) C ₃ -C ₅ -cycloalkyl,

R ^7a and R ^7b are each H,

R ^8a and R ^8b are each independently

a) H,

b) C ₁ -C ₄ -alkyl optionally substituted with COOR ⁴ , OCOR ^4a , OH or aryl,

c) C ₂ -C ₄ -alkenyl,

d) -OH,

e) -NO ₂ ,

g) -C ₁ -C ₄ -alkoxy,

i) -NR ⁴ R ²³ ,

j) halo (Cl, F, Br),

k) -CF ₃ ,

l) -CO ₂ R ⁴ ,

m) -CO-aryl as defined above,

_{n) -S (O) xC 1} -C 4 - alkyl,

o) -SO ₂ -NH-C ₁ -C ₄ -alkyl,

p) -SO ₂ -NH-allyl as defined above,

r) aryl as defined above or

s) NR ⁴ CONR ⁴ R ²³ ,

X is a single bond,

r is 1;

Specifically, the aspect of general formula (I) of this invention

R ¹ is a) -COOH,

c) -NH-SO ₂ -CF ₃ ,

d) SO ₂ NH-heteroaryl as defined above,

e) -SO ₂ NH-CO-R ²³ or

f) -CONH-SO ₂ R ²³ ,

E is a single bond,

r is 1,

R ^2a , R ^2b , R ^3a and R ^3b are each H, —C ₁ -C ₆ -alkyl, —C ₂ -C ₄ -alkynyl, —Cl, F, —NO ₂ or —CF ₃ ,

R ⁶ is —C ₁ -C ₄ -alkyl, -cyclopropyl, -CH ₂ CH ₂ CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -C ₂ -C ₅ -alkenyl or -cyclopropylmethyl,

R ^8a and R ^8b are each independently H, -C ₁ -C ₄ -alkyl, -NO ₂ , -NR ⁴ R ²³ , -OCH ₃ , -NR ⁴ COOR ²³ , -Cl, -CH ₂ COOH, -S (O) xC ₁ -C ₄ -alkyl, NR ¹⁰ CONR ⁴ R ²³ , CH ₂ OCH (C ₁ -C ₄ -alkyl), NR ⁴ COR ²³ , CO ₂ R ⁴ or -F.

More specifically, embodiments of the general formula (I) of the present invention

R ¹ is a) -COOH,

c) -SO ₂ NHCOR ²³ ,

d) -CONHSO ₂ R ²³ or

e) -NHSO ₂ CF ₃ ,

R ^2a , R ^2b , R ^3a and R ^3b are each H, —C ₁ -C ₄ -alkyl, —Cl or fluorine,

R ⁶ is -n-propyl, ethyl, -n-butyl, -trans-2-butenyl, CH ₂ CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ CF ₃ , -cyclopropyl or -cyclopropylmethyl,

R ^8a and R ^8b are each independently H, —NO ₂ , —C ₁ -C ₄ -alkyl, -NH ₂ , -NHCOCH ₃ , -S (O) x- (C ₁ -C ₄ -alkyl),- N (CH ₃ ) ₂ , -OCH ₃ , -NHCOCH ₂ NH ₂ , -NHCOCH ₂ N (CH ₃ ) ₂ , -COOH, -COOCH ₃ , -CH ₂ OCHCH ₃ , Cl, -CH ₂ COOCH ₃ , -N (R ⁴ ) CON (R ⁴ ) ₂ , —N (R ⁴ ) CO ₂ R ⁴ , —CH ₂ COOH, —OCH ₃ , CH ₂ OH or NHMe.

The second embodiment

K is -C (0)-and:

J and L are compounds of the general formula (1) which together form an aromatic ring having 6 carbon atoms substituted with R ^7a , R ^7b , R ^8a and R ^8b .

The classes and subclasses of this embodiment are as defined above.

Subclasses of compounds include

ㅍ

The third embodiment is

K is-(C = NR ²² )-and:

J and L are compounds of the general formula (1) which together form an aromatic ring having 6 carbon atoms substituted with R ^7a , R ^7b , R ^8a and R ^8b .

The classes and subclasses of this embodiment are as defined above.

Subclasses of compounds include

(1) 2-butyl-6-methyl-3 [(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4- (3H) -one; or

(2) 2-n-butyl-6-methyl-3-[(2 '-(tetrazol-5-yl) [1,1']-biphenyl-4-yl) methyl] quinazolin-4 (3H )-On.

[Acronyms Used in Reaction Schemes]

DMAP dimethylaminopyridine

-OTs p-toluenesulfonate

-OTf trifluoromethanesulfonate

DMF Dimethylformamide

DBU 1,8-diazabicyclo [5.4.0] undecane

FABMS Fast Atomic Impact Mass Spectrum

THF tetrahydrofuran

DMSO Dimethylsulfoxide

EtAc ethyl acetate

HOAc acetic acid

TFA trifluoroacetic acid

Scheme 1 shows the preparation of 1,2-disubstituted quinazolin-4 (1H) -one of general formula (1) wherein J is -C (O)-and E is a single bond. Properly substituted anthranilonnitrile is acylated using the required acyl chloride. The resulting amides are alkylated using sodium hydride and appropriate alkyl halides (or similar halides). The resulting tertiary amide is then transposed / closed using basic H peroxide ¹ . 2-substituted quinazolin-4- (1H) -one (6), wherein E is a single bond and K is -C (O)-, can be prepared from substituted anthranironitrile as in Scheme 1. Appropriately substituted anthranironitrile is acylated with the required acyl chloride to afford Compound (2), which is then ring closed with basic H peroxide to afford Compound (6).

More preferred alkylating agents (9a) and (9b), benzyl halides (3) comprising Scheme 2 can be prepared as described in European Patent Applications 253,310 and 291,969 and references cited therein. However, preferred methods for preparing biphenyl precursors (8a), (8b) and (8c) using Ni (0) or Pd (0) catalyzed crosslinking reactions are described in E. Negishi, T. Takahashi, and AO King, Org, Synthesis, 66, 67 (1987)] are summarized in Scheme 2. As shown in Scheme 2, 4-bromotoluene (4a) is treated with tert-BuLi, followed by addition of ZnCl ₂ solution to give an organic zinc compound (6a). Subsequently, compound (6a) is cured with (7a) or (7b) in the presence of a Ni (PPh ₃ ) ₂ Cl ₂ catalyst to give the desired non-pentilated compound (8a) or (8b) (PPh ₃ = trienylphosphine ) Similarly, 1-iodine-2-nitro-benzene (7c) was prepared by treating Pd (PPh ₃ ) ₄ catalyst with Cl ₂ Pd (PPh ₃ ) ₂ with (i-Bu) ₂ AlH (2 equiv) Coupling with an organic zinc compound (6a) in the presence of yields a biphenyl compound (8c). These precursors (8a), (8b) and (8c) are converted into halomethylbiphenyl derivatives (9a), (9b) and (9c) according to the methods described in EP-As 253,310 and 291,969, respectively. . When further substitution occurs in the second phenyl ring (R ^2a , R ^2b H), a preferred method for preparing biphenyl precursors (8d) and (8e) using Pd (O) catalyzed crosslinking reactions [see JK Stille, Angrew, Chem. Int. Ed. Engl., 25, 508 (1986)] is summarized in Scheme 2a. As shown in Scheme 2a, p-dolyltrimethyltin (6a) is coupled with (7d) or (7e) in toluene refluxed in the presence of 5 mol% Pd (PPh ₃ ) ₄ to give the desired biphenyl compound ( 8d) and 8e). Table I shows the synthetic compatibility of the experimental design. Compounds 8d (R ² = NO ₂ ) and (8e) (R ² = NO ₂ ) can be converted to their respective chlorides by treatment with catalytic hydrogenation, diazotization and cuprous chromosome. Biphenyl fluorides, which cannot be obtained by direct coupling to fluoroarylbromide, are reduced to (8d) (R ² = NO ₂ ) and (8e) (R ² =) by reduction, formation of diazonium tetrafluoroborate salts and pyrolysis. NO ₂ ). These precursors (8d) (R ₂ = NO ₂ or F or Cl) and (8e) (R ² = NO ₂ or F or Cl) are then prepared according to the methods described in European Patent Application Nos. 253,310 and 292,969. Converted to halomethylbiphenyl derivatives (9d) and (9e), respectively.

Scheme 3 illustrates another method for preparing 2-substituted quinazoline-4 (3H) -silver (6) starting with the corresponding anthranilic acid. Suitably substituted anthranilic acid (10) together with DMAP and triethylamine are treated at 0 ° C. with 2 equivalents of the desired acyl chloride in DMF. Then heated to 110 ° C. for 2 hours, then excess ammonium carbonate is added ² .

Scheme 4 shows a general process for the preparation of 2,3-disubstituted quinazolin-4 (3H) -one (IIa) of formula (1), wherein E is a single bond and K is -C (O)-. Sodium hydride and suitable alkyl halides (or similar halides) are used to alkylate the appropriately substituted 2-substituted quinazolin-4 (1H) -one (6) (see Scheme 1 or Scheme 3). O-alkylation products are sometimes produced in the reaction, but are generally less than 20% of the separated reaction products.

Schemes 5, 6 and 7 provide different reaction pathways for compound 11b of formula (I) wherein E is single bond, K is -C (O)-and r is 1 or 2.

Two preparation methods of 3,1,4-benzoxazone (10) are shown in Scheme 5. Substituted anthranilic acid (10) can be acylation and ring closure by heating with acyl chloride, triethylamine and DMAP in DMF ³ . Alternatively, they can also be prepared by heating an appropriately substituted anthranyl (13) with acyl chloride in pyridine ⁴ .

The required alkyl amines can then be prepared from alkyl halides (or similar halides) using standard literature methods (Scheme 6) ⁵ . Amines with r = 2 can be prepared from (9a-e) using methods known to those skilled in the art using suitable protecting groups for R ¹ , R ^2a , R ^2b , R ^3a and R ^3b . . The amine and 3,1,4-benzooxazone are then heated together to give the desired 2,3-disubstituted quinazolinone (11b) (Scheme 7).

if r = 1

a) LiN ₃ / DMSO

b) P (Ph) ₃ . H ₂ O

if r = 2

a) Na ⁺ -CH ₂ NO ₂ , DMF

b) H ₂ , 10% Pd / C

A substituted 2-alkylthioquinazolin-4 (3H) -one (15), wherein K is -C (O)-and E is -S-, is prepared from its corresponding substituted anthranilic acid as shown in Scheme 8. can do. The amine 14 in Scheme 6 can be converted to isothiocyanate 16 when treated with thiophosgen. This can then be reacted with a suitably substituted anthranilic acid to give the desired 3-alkyl-2-mercapto-quinazolin-4 (3H) -one (17) ⁶ . Then, the mud 15 is obtained ⁷ .

Similarly, a 2-alkoxy quinazolin-4 (3H) -one in which K is -C (O)-and E is -O- can be prepared from its corresponding substituted anthranilic acid as shown in Scheme 9. Can be ⁸ . Subsequently, (9a-e) is alkylated according to Method ⁹ developed by Range and Scheibley with a suitable alkyl halide to give the final product 19.

Scheme 10 shows the route to isomeric 1,2-disubstituted quinazolin-4 (1H) -one (20) where J is -C (O)-and E is S or oxygen. Anthranironitrile (1) is acylated with alkylhaloformate or alkylthiol haloformate to give (21) ¹⁰ . Subsequently, the alkylating it to the deprotonation and the appropriate alkyl halide to give the intermediate carbamate of the nitrile ^{(22). 11.} Treatment of this material with basic H peroxide can convert the intermediate to give the desired product 20.

Scheme 11 shows how a 2-amino-3-alkylquinazolinol (23) can be prepared. The 2-mercaptogitazoline (17) shown in Scheme 8 can be treated with sulfuryl chloride to give the corresponding 2-chloroquinazolinone (24) ¹² . Substitute the chloride with R ⁶ amine to afford (23) with E = NH ¹³ .

Scheme 12 shows how a 2-amino-1-alkylquinazolinone (24) can be prepared. When the first R ⁶ is a protecting group such as benzyl or tert-butyl, the product 20 from Scheme 10 where E is sulfur can be used as synthetic intermediate ¹⁴ . Deprotection of the 2-mercapto-1-alkyl-quinazolinone produced under the same conditions as used in Scheme 11 results in the formation of the desired 2-amino-1-alkylquinazolinone. Alternatively, as shown in Scheme 13 can be substituted directly into the sulphide R ₆ amine (R ⁶ can not help in -S-NH ₂ and R-NH ₂ R ₆ is the same or not the same).

Scheme 14 shows a process for preparing quinazoline-4 (3H) -imine (27). The action of Lewesson's reagent can convert 3- or unsubstituted quinazolin-4 (3H) -one (25) to quinazolin-4 (3H) -thione (26). Heating with addition of an amine results in the formation of imine 27 as shown.

Compounds of formula (I) wherein R ¹ is -CONHSO ₂ R ²³ , wherein R ²³ is alkyl, aryl or heteroaryl, can be prepared from the corresponding carboxylic acid derivatives 28 as shown in Scheme 15. The carboxylic acid 28 obtained as described in Scheme 4 can be converted to the corresponding acid chloride by treatment with refluxed thionyl chloride or preferably with oxalyl chloride and a catalytic amount of dimethylformamide at low temperature. See AW. Burgstahler, LO Weigel, and CG Shaefer-Synthesis, 767, (1976). The acid chloride can then be treated with an alkali metal salt of R ²³ SO ₂ NH ₂ to form the desired acylsulfonamide 29. Alternatively, these acylsulfonamides can also be prepared from carboxylic acids using N, N-diphenylcarbamoyl anhydride intermediates. FJ Brown et al, European Patent Application, EP 199543: KL Shepard and W. Halczenko -J. Het. Chem., 16,321 (1979). Preferably, the carboxylic acid can be converted to an acyl-imidazole intermediate and then treated with suitable aryl or alkylsulfonamides and diazabicycloundecane (DBU) to give the desired acylsulfonamides (29). [JT Drummond and G. Johnson. Tet, Lett., 29, 1653 (1988).

Formula (I) compounds wherein R ¹ is SO ₂ NHCOR ²³ can be prepared as shown in Scheme 16. The nitro compound 8c (prepared as described in Scheme 2) is reduced to the corresponding amino compound, converted to an aromatic diazonium chloride salt, and then reacted with sulfur dioxide in the presence of a copper (II) salt to give the corresponding arylsulfonyl chloride (30) can be formed. See H. Meerwein, G. Dittmar, R. Gollner, K. Hafner, F. Menech and O. Steifort, Chem. Ber., 90, 841 (1957): AJ Prinsen and H. Cerfontain, Recueil, 84, 24 (1965): EE Gilbert, Synthesis, 3 (1969) and references cited therein]. Sulfonyl chloride is reacted with ammonia in an aqueous solution or in an inert organic solvent or described in FH Bergheim and W. Baker, J. Amer. Chem. Soc., 66, (1944), 1459. By reaction with anhydrous powdered ammonium carbonate [EH Huntress and JS Autenrieth, J. Amer. Chem. Soc., 63 (1941), 3446: EH Huntress and FH Carten. J. Amer. Chem. Soc. 62, (1940), 511 sulfonamide (31) can be formed. Benzyl bromite 33 can be prepared from sulfonamide 31 as shown in Scheme 16 and can be reacted with alkali metal salts of suitable heterocyclic compounds to form the major sulfonamide 34. Sulfonamide 34 may also be prepared from aromatic sulfonyl chloride 39, which may be prepared from aryl amine 38 as shown in Scheme 17. (34) may be acylated with a suitable acyl chloride (or acyl-imidazole or other acylating agent) to give the desired acylsulfonamide 35.

Compounds wherein R ¹ is —SO ₂ NHR ²³ , wherein R ²³ is heteroaryl, may be prepared by reacting an aromatic sulfonyl chloride 39 with a suitable heteroaryl amine as shown in Scheme 17. Sulfonyl chloride 39 may be a preferred intermediate for the synthesis of compounds of this class. Sulfonyl chloride 39 may be a preferred intermediate for the synthesis of compounds of this class. Aromatic sulfonyl chloride can also be prepared by reacting the sodium salt of aromatic sulfonic acid with PCI ₅ or POCI ₃ (CM Suter, The Organic Chemistry of Sulfur, John Wiley Sons, 459, (1944)). Aromatic sulfonic acid precursors can be prepared by chlorosulfonating an aromatic ring with chlorosulfonic acid. See, EH Huntress and FH Carten. J. Amer. Chem. Soc. 62, 511 (1940)]

Biaryl sulfonamides (31) and (32) (as described in Scheme 16) can be prepared differently as shown in Scheme 18 using a palladium (0) catalyzed crosslinking coupling reaction of a suitable aryl organotin precursor. JK Stille, Pure Appl. Chem., 57 1771 (1985): TR Baiely. Tet. Lett., 27, 4407 (1986): DA Widdowson and YZ Zhang, Tetrahedron, 42, 2111 (1986)]. Organic tin compound 42 obtained from aromatic precursor 41 (SM Moerlein, J. Organometallic Chem., 319, 29 (1987)) is catalyzed by Pd (PPh ₃ ) ₄ or (PPh ₃ ) ₂ PdCl ₂ Coupling with aryl sulfonamides (44) and (45) can be used to obtain biaryl sulfonamides (31a) and (32), respectively. Similarly, benzyl bromide 50a and 60b can be prepared differently from suitable organic tin precursors 48 using a Pd (0) catalyzed crosslinking coupling reaction as shown in Scheme 19.

Compounds wherein R ¹ is —CH ₂ SO ₂ NHCOR ²³ and —CH ₂ SO ₂ NHR ²³ may be prepared as shown in Scheme 20. The main precursor aryl-methanesulfonyl chloride (56) reacts arylmethylmagnesium chloride (55) and sulfuryl chloride obtained from the corresponding benzyl chloride (52). SN Bhattancharya, C. Earborn and DPM Walton, J. Chem. Soc. C. 1265 (1968) or oxidize aryl-methylthioacetate 54 (prepared from benzyl bromide 53 and chlorine in the presence of traces of water). See Bagnay and Dransch, Chem. Ber. 93, 784 (1960)]. Alternatively, aryl-methylthioacetate 54 can be oxidized to sulfuryl chloride in the presence of acetic anhydride to form arylmethylsulfinyl chloride, see S. Thea and G. Cevasco, Tetra. Lett., 28, 5193 (1987), which may be further oxidized with a suitable oxidant to give sulfonyl chloride 56. Compounds 57 and 58 can be obtained by reacting sulfonyl chloride 56 with a suitable amine.

Compounds wherein R ¹ is -NHSO ₂ NHR ²³ can be prepared by reacting a suitable primary amine with sulfamide (60) as described in Scheme 21 (SD McDermott and WJ Spillane, Synthesis, 192 (1983)). have. Compound (60) was prepared by treating the corresponding N-tert-butyl sulfamide (59) with trifluoroacetic anhydride. See JD Catt and WL Matier, J. Org. Chem., 39 566 (1974)], and compound (59) can be prepared by reacting aromatic amine (38) with tert-butylsulfamoyl chloride (WL Matier, WT Comer). and D. Deitchman, J. Med. Chem., 15, 538 (1972)].

Another functionalization of the compound of formula (1) wherein R ^8a or R ^8b is nitro can be carried out via the following route (Scheme 22). The nitro group of compound 62 may be reduced to amine 63 by reducing under H to palladium on carbon. The amine can then be acylated with acid chloride under basic conditions to produce the amide. Acylation of the amine with chloroformate is optimally performed in the presence of sodium hydride to form an anilinium anion. This anion reacts rapidly with chloromate to produce carbamate 64. The carbamate is isolated and then lithium hexamethyldisilaziderotal protonated and alkylated to yield N, N-dialkylated carbamate 65. Alternatively, the process involves first forming an anilinium anion in one vessel, acylating it, then deprotonating in situ, and then alkylating it with R ⁴ iodide grum to produce compound (65). Can be done. The amine slowly reacts with isocyanates to form urea 66. Trisubstituted urea 67 can be prepared by treating benzyl carbamate 64 (R ²³ = benzyl) with magnesium of a secondary amine. Trisubstituted urea is deprotonated with lithium hexamethyldisilazide and alkylated with R ⁴ iodide to give N-alkylation to give compound (68). Amines may also be derivatized or converted to other groups by chemical processes well known to those skilled in the art.

[References Cited in Scheme]

Those skilled in the art will appreciate that the protecting groups used in such synthesis should be selected to suit the subsequent reaction conditions. Finally, the protecting groups are removed to give the active compound of formula (I). For example, R ¹ as carbolyl is often protected as its tert-butyl ester, which is removed by treatment with trifluoro acetic acid in the final step. Treatment with aqueous acetic acid overnight is the preferred method for removing the trityl protecting group to release the R ¹ tetrazole group.

The compounds of the present invention form various inorganic and base salts and salts of organic and base salts, which are also within the scope of the present invention. Such salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glu Carmine), arginine, lysine and the like. In addition, salts with organic and inorganic acids can be prepared, for example, by HCI, HBr, H ₂ SO ₄ , H ₃ PO ₄ , metalsulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid, camphorsulfonic acid. Physiologically acceptable non-toxic salts are preferred, but other salts are also useful in separating or purifying the product.

The salt is reacted with, or reacted with, one or more equivalent bases or acids in a free acid or free base form product in a solvent or medium in which the salt does not dissolve or in a solvent such as water removed by vacuum or lyophilization. The cation can be formed by conventional methods such as exchange with another cation in a suitable ion exchange resin.

Angiotensin II (AII) is a potent arterial vasoconstrictor and shows activity by interacting with special receptors on cell membranes. The compounds described in the present invention act as competitive antagonists of AII at the receptor. To identify AII antagonists and measure efficacy in vitro, the following two ligand-receptor binding assays are performed.

Receptor binding assay using rabbit aortic membrane preparation

Three frozen rabbit aorta (purchased from Pel-Freeze Biologicals) are suspended in 5 mM Tris-0.25 M Strozes, pH 7.4 buffer (50 ml), homogenized and centrifuged. The mixture is filtered through cheescolth and the supernatant is centrifuged at 20.000 rpm for 30 minutes at 4 ° C. The pellets thus obtained are resuspended in 30 ml of 50 mM Tris-5 mM MgCl ₂ buffer containing 0.2% bovine serum albumin and 0.2 mg / ml bacitracin and the suspension is used for 100 assay tubes. Two samples tested for screening are prepared. To the membrane sample (0.25 ml) was added ¹²⁵ I-Sar ¹ Ile ⁸ -Angiotensin II (purchased from New England Nuclear) (10 μl: 20,000 cpm) with or without a test sample and the mixture at 90 ° C. for 90 minutes. Incubate. The mixture is then diluted with ice cooled 50 mM Tris-0.9% NaCl (pH 7.4) (4 ml) and filtered through a glass fiber filter (GF / B Whatman diameter 2.4). The filter is impregnated into a scintillation cocktail (10 ml) and radioactivity is measured using a Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC ₅₀ ) of a potential AII antagonist that translocates 50% of the specific bound whole ¹²⁵ I-Sar ¹ Ile ⁸ -Angiotensin II is provided as a measure of the efficacy of a compound such as an AII antagonist.

[Receptor analysis using bovine adrenal cortex sample]

The bovine adrenal cortex is selected as the AII receptor source. Weighed tissue (0.1 g required for 100 assay tubes) is suspended and homogenized in Tris-HCI (-50 mM), pH 7.7 buffer. The homogenate is centrifuged at 20,000 rpm for 15 minutes. Discard the supernatant and resuspend the pellet in a buffer [Na ₂ HPO ₄ (10 mM) -NaCl (120 mM) -2 sodium EDTA (5 mM) containing phenylmethanesulfonyl fluoride (PMSF) (0.1 mM)] (compound). For the selection of, usually two tubes are used). To the membrane sample (0.5 ml) is added ³ H-Angiotensin II (50 mM) (10 μl) with or without test sample and the mixture is incubated at 37 ° C. for 1 hour. The mixture is then diluted with Tris buffer (4 ml) and filtered through a glass fiber filter (GF / B Whatman Diameter 2.4). The filter is immersed in a scintillation cocktail (10 ml) and radioactivity is measured using a Packcard 2660 Tricarb liquid scintillation counter. Inhibitory concentrations (IC ₅₀ ) of potential AII antagonists that displace 50% of all, in particular bound ³ H-angiotensin II, serve as a measure of the potency of compounds such as AII antagonists.

Potential antihypertensive effects of the compounds described herein can be assessed by the following methods:

Charles River Sprague-Dawley male red (300-375 g) is anesthetized with mesohextal (Brevital: 500 mg / kg i.p.) and a PE 205 tube is inserted into the trachea. A stainless steel cerebrospinal fluid rod (1.5 mm thick, 150 mm long) is inserted through the orbit of the right eye to the spine. Immediately place rats in Harvard Rodent Ventilator (speed-60 strokes / minute, 1.1 cc per 100 g volume). Ligation of the right carotid artery, incision of both the left and right vagus nerves, intubation of a PE 50 tube into the left carotid artery for drug administration, followed by information from a rectal temperature probe and a thermo pad that regulates the temperature 37 Keep at ℃. Atropine (1 mg / kg i.v.) is then administered, and 15 minutes later propranols (1 mg / kg i.v.) are administered. After 30 minutes, angiotensin II or other antagonist is administered intravenously at 30 minute intervals, and the increase in diastolic blood pressure is measured before and after drug or excipient administration.

Using the methods described above, evaluation of representative compounds of the present invention has revealed that they exhibit at least IC _{50 50} μM activity, thereby confirming and demonstrating the usefulness of the compounds of the present invention as effective AII antagonists.

Thus, the compounds of the present invention are useful for treating hypertension. They are also useful for the treatment of acute and chronic congestive heart failure. These compounds also include secondary hyperaldosteroneism, primary and secondary pulmonary hyperaldosteroneism, primary and secondary pulmonary hypertension, renal failure (eg, diabetic nephropathy, glomerulonephritis, sclerosis, glomerulosclerosis, proteinuria of primary kidney disease, end stage kidney disease, kidney transplant). It is useful for the treatment of neovascular hypertension, left ventricular dysfunction, diabetic retinopathy, and vascular diseases such as migraine, Raynaud's disease, and caliber hyperplasia, and is expected to minimize the progression of atherosclerosis. The application of the compounds of the present invention to these and similar diseases will be apparent to those skilled in the art.

The compounds of the present invention are also useful for treating intraocular pressure elevations and increasing retinal blood flow, and are common pharmaceutical formulations (e.g. tablets, capsules, injections) and liquids, ointments for patients in need of such treatment. It can be administered as a topical ophthalmic preparation in the form of, an insert and a gel. Pharmaceutical formulations prepared for the treatment of intraocular pressure usually contain about 0.1%, preferably 0.5-2% by weight of the compound of the present invention.

In treating high blood pressure and the above-mentioned clinical conditions, the compounds of the present invention can be used in compositions such as tablets, capsules or elixirs for rectal administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. Can be. The compounds of the present invention can be administered at a dose that provides optimal pharmaceutical efficacy to patients (animals and humans) in need of such treatment. Dosages may vary from patient to patient, depending on the nature and severity of the disease, the patient's weight, the particular diet the patient is performing, concurrent medications and other factors recognized by those skilled in the art, but the dosage range is generally per patient. About 1 to 1000 mg per day, which may be administered in a single dose or in divided doses. Preferably the dosage range is about 2.5 to 250 mg, more preferably about 2.5 to 75 mg per patient per day.

The compounds of the present invention may also be administered in admixture with other hypertension therapeutics and / or diuretics and / or angiotensin convertase inhibitors and / or calcium blockers. For example, the compounds of the present invention may be selected from the group consisting of amylolide, atenolol, bendroflumetiazide, chlorothalidone, chlorothiazide, clonidine, cryptotenamine acetate, and cryptoteamine tannate, deserpidine, dias Said, guanetidensulfate, hydralazine hydrochloride, hydroclothiazide, metolazone, metoprolol tartrate, methiclothiazide, methyldopa, methyldopate hydrochloride, mimocidyl, pargiline hydrochloride, polythiazide, Prazosin, propranolol, laubolpia, rauwolfia serpentina, rescinamine, reserpin, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimetaphan chamlate , Benzthiazide, quinetazone, ticlinapan, triamterene, acetazolamide, aminophylline, cyclothiazide, etaclean Acids, furosemide, meretoxylin procaine, sodium ethacrineate, captopril, delapril hydrochloride, enalapril, enalprilat, posinopril sodium, ricinopril, pentopril, quinapril hydrochloride , Compounds such as ramipril, teprotide, jofenoprilcalcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine and nirendipine, as well as their It can be administered in admixture with mixtures and combinations.

Typically, the daily doses for these combinations may vary from about 1/5 to the maximum recommended dose of the clinical minimum recommended dose relative to the total amount when they are administered alone.

To illustrate these combinations, one of the minute invention angiotensin II antagonists of 2.5 to 250 mg per day, which is clinically effective, can be effectively combined with the following compounds in the following daily dose ranges at levels of 0.5 to 250 mg per day: Examples: hydrochlorothiazide (15-200 mg), chlorothiazide (125-2000 mg), ethacrynic acid (15-200 mg), amylolide (5-20 mg), murosemide (5-80 mg), propranolol ( 20-400 mg), timolol maleate (5 to 60 mg), methyldopa (65 to 2000 mg), felodipine (5 to 60 mg), nifedipine (5 to 60 mg) and nirenedipine (5 to 60 mg). In addition, hydrochlorothiazide (15 to 200 mg) + amylolide (5 to 200 mg) + angiotensin II antagonist (3 to 200 mg) or hydrochlorothiazide (15 to 200 mg) + timolol maleate (5 to 200 mg) of the present invention. 60 mg) + angiotensin II antagonist (0.5 to 250 mg) or hydrochlorothiazide (15 to 200 mg) + nifedipine (5 to 60 mg) + angiotensin II antagonist (0.5 to 250 mg) of the present invention, three drug combinations of hypertension It is an effective combination for controlling blood pressure in patients. Originally, these dose ranges can be adjusted on a per-unit basis to allow for multiple doses per day, and as indicated above, doses will vary depending on the nature and severity of the disease, the weight of the patient, the particular diet and other factors. will be.

Typically, these combinations can be formulated into pharmaceutical compositions as discussed below.

About 1 to 100 mg of a compound of formula (I), or mixtures thereof, or physiologically acceptable salts thereof, may contain physiologically acceptable excipients, tints, excipients, binders, preservatives, stabilizers, flavoring agents. And in unit dosage forms as required for acceptable pharmaceutical practice. The amount of active substance in these compositions and formulations is such that an appropriate dose within the ranges indicated is obtained.

Examples of adjuvants that may be incorporated into tablets, capsules and the like include: binders (eg tragacanth gum, acacia, corn starch or gelatin); Excipients such as microcrystalline cellulose; Disintegrants (eg corn starch, pregelatinized starch; alginic acid, etc.); Glidants (eg magnesium stearate); Sweetening agents such as sucrose, lactose or saccharin; Flavoring agents, for example peppermint, winter green oil or cherry oil. When the unit dosage form is a capsule, it may contain a liquid carrier (eg fatty oil) in addition to the material of the above form. Various other materials may be present as the skin or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. Syrups and elixirs may contain the active compound, sucrose as a sweetener, methyl and propylparabens as preservatives, pigments and flavoring agents (cherry and orange flavors).

Injectable sterile compositions can be prepared by dissolving or suspending the active substance in distilled water for injection, natural vegetable oils (e.g. sesame oil, coconut oil, peanut oil, cottonseed oil, etc.) or synthetic fatty excipients (e.g. ethyl oleate, etc.) It may be formulated according to pharmaceutical practice. If necessary, buffers, preservatives, antioxidants and the like may be incorporated.

The following examples describe the preparation of the compounds of formula (I) and their incorporation into pharmaceutical compositions, and are not intended to limit the invention set forth in the appended claims to these examples. All ¹ H-NMR spectra are recorded with a Varian XL-300 Fourier Transform Spectrometer. Chemical shifts are reported as ppm downfield from tetramethylsilane. The vaginal mass spectra were measured by the Mass Spectrum Department of The Merck and Company (NJ Rahway). Analytical TLC is a. M. Observed by UV visualization in a pre-coated silica plate of EM Marck (glass, 0.25 mm, Kieselgel 60F 254). All chromatography was done. M. Performed with Merck's silica gel. All bangs are run under anhydrous nitrogen atmosphere under standard conditions for those skilled in the art.

[Production of Biphenyl Synthetic Intermediates]

[2-3-grade-butoxycarbonyl-4'-methylbiphenyl]

At −78 ° C., a solution of p-bromotoluene (30 g) in anhydrous ether (150 ml) is added dropwise a solution of tert-BuLi (210 ml) in pentane (1.7 M) over a period of 1.5 hours using a fennel. The bath is then removed and the mixture is stirred for an additional 2 hours at room temperature. The contents of the flask are then slowly added (using cannula) to a premixed ZnCl ₂ solution in ether (1M, 180 ml) and dry THF (360 ml) at room temperature. The mixture was stirred at room temperature for 2 hours, and the slurry was then stirred for a solution of 2-3-butoxy carbonyl iodobenzene (35.6 g) and NiC ₂ (Ph ₃ P) ₂ (2.1 g) in dry THF (360 mL). (Using cannula). The mixture is stirred overnight at room temperature (18 hours) and slowly poured into ice cold 0.5N HCl (1500 ml) with stirring. The organic layer is separated and the aqueous layer is extracted with ether (3 x 300 ml). The combined organic layers are washed with water, brine and dried over magnesium sulfate. The solvent is removed to give crude product (32 g) as an oil. This material was purified on a silica gel effluent column using ethyl acetate-hexane (1:12) to afford the title compound (24 g, 76%) as an oil.

[4-Bromomethyl-2'-tert-butoxycarbonylbiphenyl]

Freshly-opened N-bromosuccinimide (17.6 g, 0.099 mmol) and dibenzoyl in a 2-3-butoxycarbonyl-4'-methylbiphenyl (25.3 g, 95 mmol) solution in CCl ₄ (200 ml) Peroxide (2.28 g, 0.0094 mmol) is added. The mixture is refluxed for 4 hours, cooled to room temperature and filtered. The filtrate is washed with saturated NaHSO ₃ (1 × 50 ml), saturated NaHSO ₃ (1 × 50 ml), water (1 × 50 ml), saturated NaCl (1 × 50 ml) and dried over magnesium sulfate. The solution is filtered and concentrated in vacuo. The residue is dissolved in 100 ml of hot hexane. As the solution cools, crystals form slowly. The flask is finally cooled to -20 ° C and the precipitate is recovered by filtration. The solid is washed with ice cooled hexanes and dried in vacuo to yield 27 g (88%) of a white solid.

[2-Cyano-4'-methylbiphenyl]

At −78 ° C., to a solution of p-bromotoluene (30 g) in anhydrous ether (150 ml) is added dropwise a solution of tert-BuLi (210 ml) in pentane (1.7 M) over 1.5 hours using a fennel. The bath is then removed and the mixture is stirred for an additional 2 hours at room temperature. The flask contents are then slowly added (using cannula) to a premixed ZnCl ₂ solution in ether (1M) (180 ml) and dry THF (360 ml) at room temperature. The mixture is stirred at room temperature for 2 hours and then slurry is added to a solution of 2-bromobenzonitrile (21.3 g) and NiCl ₂ (Ph ₃ P) ₂ (2.1 g) in dry THF (300 ml) (using cannula). . After stirring overnight at room temperature (18 hours), the mixture is slowly poured into ice cold 1N HCl (1500 ml) with stirring. The organic layer is separated and the aqueous layer is extracted with ether (3 x 300 ml). The combined organic layers are washed with water, brine and then dried over magnesium sulfate. Removal of solvent gives crude product (34 g) as a semi solid material. This material was purified on a silica gel effluent column using ethyl acetate-hexane (1:12) to afford the desired nitrile low melting solid (28 g, 88%).

[Trimethylstannyl azide]

To a concentrated solution of NaN 3 (1.2 kg, 18.5 mmol) in water (3 L) was added a trimethyltin chloride (600 g, 3 mmol) solution in dioxane (400 ml) in 3 portions with vigorous stirring. A precipitate immediately forms. After stirring overnight at room temperature, the mixture is filtered. The residue is washed with water, dried by suction and then vacuum dried with phosphorus pentoxide.

[5- [2- (4'-methylbiphenyl)] tetrazol]

At room temperature, trimethyltin azide (525 g, 2.55 mmol) is added to a solution of 2-cyano-4'-methylbiphenyl (390 g, 2.02 mmol) in toluene (2.3 L). The mixture is refluxed for 24 hours, cooled to room temperature, filtered, washed with toluene and then suction dried in a funnel. The precipitate is resuspended in toluene (3.5 L) and THF (250 ml) is added. Anhydrous CHl is bubbled at normal speed at room temperature to give a clear solution (45 min). After adding HCl gas, it is stirred for 20 minutes to form a white solid. The reaction mixture is stirred overnight. The solid product is filtered off, washed with toluene and then ether and then dried in vacuo. 250 g (53%) of tetrazole having a melting point of 152-154 占 폚 is obtained.

[N-triphenylmethyl-5- [2- (4'-methylbiphenyl)] tetrazol]

At room temperature, triphenylmethylchloride (310 g, 1.11 mmol) in a suspension solution of 5- [2- (4'-methylbiphenyl)] tetrazol] tetrazole (250 g, 1.06 mmol) in CH ₂ Cl ₂ (4 L). Add. The reaction mixture is stirred and triethylamine (190 ml, 138 g, 138. mmol) is added several times. After addition, the mixture is stirred at reflux for 90 minutes. The solution is cooled to room temperature, washed with water, dried over magnesium sulfate, filtered through a silica gel plug and concentrated on a rotary evaporator to give a solid. This was crystallized with toluene to give the product (425 g, 84%) having a melting point of 166 to 168 DEG C as an off-white solid.

[N-triphenylmethyl-5- [2- (4'-bromomethylbiphenyl)] tetrazol]

To a solution of N-triphenylmethyl-5- [2- (4'-methylbiphenyl)] tetrazole (425 g, 0.89 mmol) in CCl ₄ (4.0 L), and N-bromicinimide (159 g, 0.89 mmol) and Dibenzoyl peroxide (22 g, 0.089 mmol) is added. The mixture is refluxed for 2 hours, cooled to room temperature and filtered. The filtrate is concentrated in vacuo to give a thick oil. Ether (2.0 L) was added to this oil to form a solution which was administered, followed by crystallization and filtration to give a white solid (367 g, 74%) with a melting point of 137 to 139.5 ° C;

[N-triphenylmethyl-5- [2- (4'-aminomethylbiphenyl)] tetrazole]

LiNO ₃ (1.23 g, 25 mmol) is added to a suspension of N-triphenylmethyl-5- [2- (4'-bromomethylbiphenyl)]-tetrazole (11.15 g, 22 mmol) in anhydrous DMSO (55 ml). . The mixture gradually becomes clear and is replaced by fresh white precipitate. The mixture is stirred for 6 hours and filtered. The precipitate is washed with 50 ml of water. A precipitate is further formed in the mixed filtrate; This is refiltered and the residue is washed with MeOH (30 ml) and water (100 ml). The solid product is dried under vacuum overnight. Crude azide (9.89 g, 20.8 mmol) is dissolved in anhydrous THF (50 ml) and triphenylphosphine (5.73 g, 22 mmol) is added in small portions. Generation of N ₂ is observed during the addition. After 4 hours, water (0.63 ml, 34 mmol) was added to the solution and stirred overnight. The solution is concentrated under zen pore and the residue is purified by effluent chromatography on silica gel eluting with 95: 5: 0.01 CHCl ₃ : MeOH: NH ₄ OH to give a white solid (6.83 g, 15.4 mmol). The overall yield is 69%.

[Production of further functionalized biphenyls]

[Preparation of N-triphenyl-5- (4'-bromomethyl-4-chlorobiphen-2-yl) tetazole]

[Step 1]

[2-Cyano-4'-methyl-4-nitrobiphenyl]

In a solution of p-tolyltrimethyltin (389 mg, 1.525 mmol) in anhydrous toluene (5 ml) under N ₂ , 2-bromo-5-nitro-benzonitrile (276 mg, 1.22 mmol) and Pd (PPh ₃ ) ₄ (176 mg; 10 mol) %) Is added. The reaction is stirred at reflux under N ₂ for 24 h and then cooled to room temperature. The mixture is diluted with EtOAc and the solid is removed by filtration through a pad of celite. The filtrate is concentrated in vacuo and the residue is purified by effluent chromatography on silica gel, eluting with hexanes / EtOAc (10: 1) to afford the title compound (214 mg, 74%) as a pale yellow solid.

[Step 2]

[N-triphenylmethyl-5- (4'-methyl-4-nitrobiphen-2-yl) tetrazol]

The title compound is prepared according to the method of EP 0,291,969 using 2-cyano-4-nitro-4'-methylbiphenyl (step 1) as starting material.

[Step 3]

[N-triphenylmethyl-5- (4-chloro-4'-methylbiphen-2-yl) tetrazol]

A solution of N-triphenylmethyl-5- (4'-methyl-4-nitrobiphen-2-yl) tetrazole (0.115 g, 0.224 mmol) in MeOH / DMF (2 ml / 12 ml) was carbon at room temperature for 1 hour Hydrogen under 40 psi H ₂ with 10% Pd phase. The reaction is filtered through celite and the filtrate is concentrated in vacuo. Triphenyl methyl group is removed during hydrogenation. The crude 4-amino compound is dissolved in glacial acetic acid (3 ml) and slowly added to a solution of NaNO ₂ (28.8 mg, 0.417 mmol) in cold concentrated sulfuric acid (1 ml). The diazonium solution is stirred well for 2 hours and then slowly added to a solution of CuCl (0.449 g; 20 equiv) in chilled (0 ° C.) concentrated HCI. The mixture is stirred for 30 minutes, then poured into H ₂ O and extracted with EtO / EtOAc. The combined organic extracts are washed with H ₂ O and brine, dried over magnesium sulfate and then concentrated in vacuo. The product was purified by effluent chromatography by eluting with hexanes / EtOAc / HOAc (80: 20: 1) on a silica gel column to give 26 mg of 5- (4-chloro-4'-methyl-biphen-2-yl) tetrazole ( 45% for step 2). Free tetrazole is dissolved in CH ₂ Cl ₂ (3.5 ml) and NEt ₃ (0.035 ml, 2.5 equiv) and Ph ₃ CCl (27 mg, 1.0 equiv) is added. After 30 minutes diluted with Et ₂ O and washed with 10% citric acid, 1N NaOH and brine. The organic layer was dried over anhydrous MgSO ₄ and concentrated in vacuo to afford 51.2 mg (100%) of crude N-triphenylmethyl-5- (4-chloro-4'-methylbiphen-2-yl) tetrazole.

[Step 4]

[N-triphenyl-5- (4'-bromomethyl-4-chlorobiphen-2-yl) tetrazol]

N-triphenylmethyl-5- (4-chloro-4'-methyl-biphen-2-yl) tetrazole (steps 1 to 3) was prepared according to the method described in EP Patent No. 0.291,969. To give the title compound.

[Production of 4-bromomethyl-2'-nitrobiphenyl]

[Step 1]

[4-Methyl-2'-nitrobiphenyl]

A 1 L three-necked 24/40 round bottom flask equipped with a mechanical stirrer, a 250 ml constant pressure addition funnel with a nitrogen inlet at the top and a septum was flame-dried, cooled and then dried in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere. Add p-bromotoluene (29.07 g, 0.17 mmol) solution. The solution is stirred, cooled to −78 ° C., and then a solution of 1.7 M tert-butyllithium (200 ml, 0.34 ml) in pentane is added through the addition funnel over 30 minutes. After the addition is complete, the cooling bath is removed and the reaction mixture is stirred for 30 minutes and then warmed to room temperature. To the dropping funnel is added 1.0M zinc chloride solution (170ml, 0.17ml) in diethyl ether and added to the reaction mixture over 10 minutes. Separate 1 l three-necked 24/40 round bottom flask equipped with mechanical stirrer, nitrogen inlet and septum was flame-dried and cooled, then bis (triphenylphosphine) palladium (II) chloride (4.04 g, 6.0 mmol) under nitrogen atmosphere ) And anhydrous tetrahydrofuran (50 ml). The stirrer is turned on and 8 ml of a 1.5 M diisobutylaluminum hydride solution (12 mmol) in toluene is added to the suspension by syringe. The catalyst is further stirred at room temperature for 10 minutes, after which a solution of 1-bromo-2-nitrobenzene (23.23 g, 0.115 mmol) in anhydrous tetrahydrofuran (100 ml) is added. The tolyzyl chloride suspension is transferred to a second flask via a large diameter cannula. The reaction mixture is further stirred at room temperature for 45 minutes, then most of the tetrahydrofuran is removed by rotary evaporation. The resulting oil is partitioned between ethyl acetate and 1.0N hydrochloric acid. The organic layer is washed successively with water and brine, then dried (MgSO ₄ ), filtered and then evaporated. The residual oil is eluted with 10% ethyl acetate-hexane in silica gel and purified by effluent chromatography and evaporated to dryness to afford the product (15.43 g, 63%) as a viscous yellow oil.

[Step 2]

[4-bromomethyl-2'-nitrobiphenyl]

4-methyl-2'-nitro [1,1'-biphenyl] (15.427 g, 72 mmol), carbon tetrachloride (1.2 L), N in a 2 L 24/40 three-neck round bottom flask equipped with a mechanical stirrer, reflux condenser and stopper Add bromosuccinimide (14.164 g, 80 mmol) and 2,2'-azobis- (2-methylpropionitrile) (0.50 g). The stirred reaction mixture is refluxed under a stream of nitrogen for 4 hours, cooled to room temperature and filtered. The filtrate is evaporated in vacuo and the residual oil is eluted with 10% ethyl acetate hexane and purified by effluent chromatography on silica gel. Pure fractions are evaporated to afford the product (7.83 g, 37%) as a yellow crystalline solid.

[Preparation of N-triphenylmethyl-5- (4'-fluoro-4'-bromomethyl-biphen-2-yl) tetrazole]

[Step 1]

[2-Cyano-4-fluoro-4'-methylbiphenyl]

A solution of p-tolyltrimethyltin (1.26 g, 4.96. Mmol) in anhydrous toluene (8 ml) is degassed with an N ₂ stream for about 5 minutes. To this solution under N ₂ is added 2-bromo-5-fluoro-benzonitrile (0.901 g, 4.51 mmol) and Pd (PPh ₃ ) ₄ (260 mg, 5 mol%). The reaction is stirred at reflux for 12 h under N ₂ and then cooled to room temperature. The reaction mixture is filtered through a pad of celite and the filtrate is concentrated in vacuo. The product was eluted with hexanes / CH ₂ Cl ₂ and purified by effluent chromatography on a silica column to give the title compound (0.606 g, 64%) as a light yellow solid.

[Step 2]

[N-triphenyl-5- (4-fluoro-4'-methyl-biphen-2-yl) tetrazol]

The title compound is prepared using 2-cyano-4-fluoro-4'-methylbiphenyl (step 1) as a starting material according to the method described in EP 0,291,969.

[Step 3]

[N-triphenyl-5- (4-fluoro-4'-bromomethyl-biphen-2-yl) tetrazol]

N-bromosuccinimide in a solution of N-triphenylmethyl-5- (4-fluoro-4'-methyl-biphen-2-yl) tetrazole (454.4 mg, 0.9161 mmol) in anhydrous CCl ₄ (8 ml) (179.2 mg, 1.1 equiv) and catalytic amount of AIBN are added. The reaction is heated to reflux (105-115 °) under N ₂ . After 3 hours, the reaction is cooled and filtered through a cotton pipette to remove succinimide formed. Remove the solvent and replace with EtOAc / Et ₂ O. The reaction is washed with 1N NaOH and brine. The organic solution is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the product. The crude product is used in the next reaction.

[Preparation of 2-alkyl-quinazolin-4 (1H) -one]

Example 1

[2-Butyl-6-methylquinazolin-4 (1H) -one]

To a solution of 2-amino-5-methylbenzoic acid (3.0 g, 20 mmol) in anhydrous DMF (20 ml) was added DMAP (200 mg) at 0 ° C., followed by triethylamine (6.07 g, 60 mmol) and valeryl chloride (5.02 g, 40 mmol) is added. The resulting mixture is stirred at 0 ° C. for 30 minutes. The mixture is heated to 110 ° C. and the formation of intermediate quinoxazolone (rf = 0.8, 40% EtAc / nucleic acid) is confirmed by TLC. When the intermediate form is complete, NH ₄ CO ₃ (10 g, 100 mmol) is carefully added. Continue heating to consume quinoxazolone and form a polar (rf = 0.4, 40% EtAc / hexane) quinazolin-4 (1H) -one. The reaction mixture is concentrated in vacuo and the residue is dissolved in ether (50 ml) and water (50 ml). The mixture is filtered, the residue is washed with ether (20 ml) and the filtrate is discarded. The residue is recrystallized from MeOH to give a white crystalline solid (1.07 g, 5 mmol) (total yield 25%).

Example 2

[6-Methyl-2-propylquinazolin-4 (1H) -one]

2-propyl derivatives are prepared in the same manner as for the preparation of 2-butyl derivatives using butyryl chloride instead of valeryl chloride. The product is recrystallized from hexane / acetone to give white crystals (yield 32%).

Example 3

[2-Butyl-7-methylquinazolin-4- (1H) -one]

Valeroyl chloride and 2-amino-4-methylbenzoic acid are obtained in the same manner as in Example 1. The product was recrystallized from MeOH to recover 0.91 g (4.2 mmol) (21% total yield).

Example 4

[2-butyl-naphtho [2, 3-e] quinazolin-4 (1H) -one]

Obtained in the same manner as in Example 1 using valeroyl chloride and 2-aminonaphthoic acid. The product is recrystallized from MeOH. Impurities are recrystallized with the desired product. ¹ H-NMR analysis showed that the impurity was 25% of the product. Recover the product (1.6 g, 59% yield).

Example 5

[2-Butyl-5-methylquinazolin-4 (1H) -1one]

The same method as in Example 1 was used with valeroyl chloride and 2-amino-6-methylbenzoic acid on a 16 mmol scale. The concentrated reaction mixture is diluted with 50 ml of ether and 5 ml of H ₂ O. The mixture is stirred for a few minutes and then vacuum filtered. Upon filtration additional crystalline material is formed in the filtrate. Filter the filtrate again. Repeat this process two more times. Collect and combine the precipitates. The ether layer is decanted from the aqueous layer and concentrated to 15 ml. Then 25 ml of hexanes are added and the mixture is filtered. The combined precipitate is recrystallized from MeOH / H ₂ O to give fluffy white crystals (0.73 g, 3.37 mmol) (yield 21%).

Example 6

[2-Butyl-6, 8-dimethylquinazolin-4 (1H) -one]

The same procedure as in Example 1 was repeated using valeroyl chloride and 2-amino-5, 8-dimethylbenzoic acid on a 12 mmol scale. The product collected from the filtrate of ether / water mixture is recrystallized from MeOH. ¹ H-NMR and TLC indicate a 50% mixture of the desired quinazoline and impurities in the isolated product. An aliquot (0.5 g) of this material is concentrated with effluent silica (5 ml) packed into an effluent chromatography column. The column is eluted with 60% EtAc / hexanes. Primary eluted compound (0.14 g) is collected as a TLC homogeneous sample of the product for the purpose.

Example 7

[2-Butyl-8-methylquinazolin-4 (1H) -one]

The same procedure as in Example 1 was repeated using valeroyl chloride and 2-amino-6-methylbenzoic acid on a scale of 1 mmol. The concentrated reaction mixture is diluted with 20 ml of ether 20 ml / H ₂ O. The mixture is filtered. The ether layer is separated, dried (MgSO ₄ ), filtered, concentrated and the residue is eluted with 50% EtAc / hexanes and subjected to effluent chromatography on silica to give a yellow solid (48 mg, 0.22 mmol) in the form of a fluffy form. (Yield 22%).

Example 8

[2-Butyl-6-isopropylquinazolin-4 (1H) -one]

The same procedure as in Example 1 was repeated using valeroyl chloride and 2-amino-5-isopropylbenzoic acid on a 16 mmol scale. The concentrated reaction mixture is partitioned between water (20 ml) and ether (20 ml). The fine white precipitate is filtered off and recrystallized from MeOH / water. The first portion yields 0.56 g of white crystals in the form of down.

Example 9

[2-Butyl-6-thiomethylquinazolin-4 (1H) -one]

Performed in the same manner as described in Example 1, but adding ether / water to the reaction mixture does not form a quinazoli precipitate. The aqueous layer is extracted with ether and the combined etheric extracts are washed with brine and then dried over magnesium sulfate. The mixture is filtered and concentrated in vacuo to give a mixture of the desired product with 2- (N-valeroyl-amino) -5-thiomethylbenzamide. The mixture is heated at 100 ° C. with 2 equivalents of a 1N NaOH solution in water until a clear solution is obtained. The solution is cooled, acidified and filtered to give a pale yellow precipitate. The product is recrystallized from MeOH to give the title compound in 73% total yield.

Example 10

[2-Butyl-6-nitroquinazolin-4 (1H) -one]

To a mixture of 2-cyano-4-nitroaniline (326 mg, 2 mmol) in CH ₂ Cl ₂ (10 ml) is added triethylamine (0.34 ml, 2.4 ml) and DMAP (25 mg) at 0 ° C. Valeryl chloride (0.26 ml) is added dropwise to the mixture. The reaction mixture is allowed to warm to room temperature over 1.5 hours and then concentrated in vacuo. The residue is dissolved in EtAc (40 ml) and washed with water (25 ml), saturated NaHCO ₃ (25 ml) and brine (25 ml). The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated. The residue (0.46 g) is purified by effluent chromatography. The residue is adsorbed onto silica (0.6 g) packed in a 5.5x0.75 silica runoff chromatography column. The product is eluted with 20% EtAc / hexanes to give N-valeryl-2-cyano-4-nitro-anilide (0.21 g, 44% yield). Amide (0.1 g, 0.42 mmol) is dissolved in MeOH (1.5 ml). To this solution is added 30% H peroxide solution (138 μl) and 3N NaOH solution (330 μl). The solution is refluxed for 1.5 h, cooled and then concentrated in vacuo. The residue is dissolved in water (10 ml). The product was precipitated as a yellow powder (90 mg, 0.36 mmol) by dropwise addition of saturated NH ₄ Cl solution (87% yield).

Example 11

[2-Butylquinazolin-4 (1H) -one]

To a solution of 2-aminobenzonitrile (4.23 mmol), triethylamine (514 mg, 5.08 mmol) and DMAP (50 mg, 0.41 mmol) in CH ₂ Cl ₂ (6 ml) over 1 minute at 0 ° C. over 1 minute at valeryl chloride (562 mg, 4.66 mmol) is added dropwise. The mixture is warmed to room temperature and stirred for 20 minutes. The mixture is then diluted with water and brine and extracted three times with ether. The combined organics are dried over magnesium sulphate, the solvent is removed in vacuo, then eluted with 20% ethyl acetate in hexane to purify by effluent chromatography to afford 2-valeramido-benzonitrile. R _f in 20% ethyl acetate in hexane is 0.22.

To a solution of amide (5.1 g) in methanol (90 ml) is added 3N NaOH (21 ml) and 30% H ₂ O ₂ (10 ml) at room temperature. The mixture is refluxed for 30 minutes and concentrated in vacuo. Water and saturated NH ₄ Cl are added and the mixture is extracted three times with ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo and the residue was recrystallized from hexane / acetone to give two products as white needles (2.2 g, 43% yield).

Example 12

[6-Bromomethyl-2-butylquinazolin-4 (1H) -one]

To the suspension of the product of Example 2 (2.6 g, 12 mmol) in anhydrous CCl ₄ (100 ml) was added N-bromosuccinimide (2.56 g) and benzoyl peroxide (200 mg). The reaction mixture is heated to reflux for 45 minutes, at which time a precipitate is formed. The reaction mixture is concentrated in vacuo and the residue is partitioned between EtAc (150 ml) and water (100 ml). The mixture is shaken and then filtered to afford the title compound (1.59 g, 45% aqueous). The filtrate is separated into two layers and the organic layer is washed with saturated NaHCO ₃ solution (75 ml), water (75 ml) and brine (75 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to the filtrate. The residue is purified by recrystallization with EtAc to give the same product (0.52 g, 1.76 mmol) as the product recovered above. Total yield 60%.

Example 13

[5-Bromomethyl-2-butylquinazolin-4 (1H) -one]

The product of Example 5 was treated as in Example 13 to yield a white solid.

Example 14

[6-Acetoxymethyl-2-butylquinazolin-4 (1H) -one]

To a solution of quinazolinone (2.1 g, 7.0 mmol) in anhydrous DMF (15 ml) prepared in Example 12 was added sodium acetate (1.74 g, 20.0 mmol). The mixture is heated at 60 ° C. for 3 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in CH ₂ Cl ₂ (100 ml). The solution is washed with water (13x20ml), brine (1x20ml) and then dried over MsSO ₄ . The residue is recrystallized from MeOH / H ₂ O to give a colorless solid (1.31 g, 4.8 mmol).

Example 15

[5-acetoxymethyl-2-butylquinazolin-4 (1H) -one]

The product of Example 13 was treated as in Example 15 to recrystallize with EtAc to afford the desired acetylated product.

Example 16

[6-Nitro-2-propylquinazolin-4 (1H) -one]

To a solution of 2-amino-5-nitrobenzonitrile (16.3 g, 0.1 mol) in CH ₂ Cl ₂ (200 ml) was added triethylamine (21 ml, 0.15 mol) at 0 ° C., followed by DMAP (0.3 g) and butyryl. Chloride (11.71 g, 0.11 mol) is added. The reaction mixture is allowed to warm up to room temperature and then heated at 50 ° C. overnight. The solution is washed with 1N HCl (1 × 20 ml), water (1 × 20 ml), saturated NaHCO ₃ (2 × 20 ml) and brine (1 × 20 ml) and dried over magnesium sulfate. The solution is filtered and concentrated in vacuo. The residue is dissolved in MeOH (200 ml), to which 5M NaOH solution (44 ml, 0.22 mol) is added followed by the dropwise addition of 30% H ₂ O ₂ (25 ml, 0.22 mol) and water (50 ml). The mixture is refluxed for 4 hours, cooled and then filtered. The filtrate is acidified with 1N HCl and the resulting precipitate is recovered by filtration. The residue is recrystallized from MeOH to give a light brown fluffy crystal (8.3 g, 0.36 mol).

[Preparation of 3-N-alkyl-2-alkylquinazolin-4 (3H) -one]

General methods for synthesizing 3-N-alkylated, -quinazolin-4 (3H) -ones are described below. Chromatographic conditions, yields and spectral data are given for compounds prepared by this method.

A suspension of NaH (1.1 mmol) in anhydrous DMF (2 mL) is treated with solid quinazolin-4 (1H) -one (1 mmol) under nitrogen at 0 ° C. (most of the quinazoline-4 (1H) -ones produced are Insoluble in DMF). It can be observed that when quinazolin-4 (1H) one is deprotonated and dissolved, H is generated immediately. After 30 minutes, the solution is warmed to room temperature for a further period. To a solution cooled to 0 ° C., 4-bromomethyl-2′-tert-butoxycarbonyl-biphenyl, 4-bromomethyl-2'-cyano-biphenyl or N- in DMF (1.5 ml). Triphenylmethyl-5-[(2- (4'-bromomethylbiphenyl)] tetrazol (1 mmol) solution is added After 30 minutes, the reaction mixture is warmed to room temperature and stirred overnight The solution is concentrated and The residue is dissolved in 50 ml of EtAc The solution is washed with water (3 × 10 ml) and brine (2 × 10 ml) The organic layer is dried over magnesium sulphate, filtered and concentrated in vacuo. do.

Example 17

[2-butyl-3 [(2 '-(tert-butoxycarbonyl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

Quinazolin prepared as described in Example 11 is alkylated with 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl. The product is purified by flash chromatography on silica gel eluting with 1% EtAc / methylene chloride.

Example 18

[2-butyl-3-[(2 '-(cyano) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

Quinazolinones prepared as described in Example 11 are alkylated with 4-bromomethyl-2'-cyano-biphenyl. The product is purified by MPLC Lobar C silica column eluting with 25% EtAc / hexanes. R _f = 0.13 (30% EtAc / hexanes)

Example 19

[2-butyl-3-[(2 '(tert-butoxycarbonyl) biphen-4-yl) -methyl] -8-methylquinazolin-4 (3H) -one]

Quinazolinones prepared as described in Example 7 are alkylated with 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl. The product is eluted with 12.5% EtAc / hexanes and forced to run chromatography on silica.

Example 20

[2-butyl-3-[(2 '-(tert-butoxycarbonyl) biphen-4-yl) -methyl] -6-methylquinazolin-4 (3H) -one]

Quinazolinones prepared as described in Example 1 are alkylated with 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl. The product is eluted with 15% EtAc / hexanes and forced to run chromatography on silica.

Example 21

[2-butyl-3-[(2 '-(tert-butoxycarbonyl) biphen-4-yl) -methyl] -6-methylquinazolin-4 (3H) -one]

Quinazolinones prepared as described in Example 10 are alkylated with 4-bromomethyl-2'-tert-butoxycarbonyl-diphenyl. The product is eluted with 20% EtAc / hexanes and forced to run chromatography on silica.

Example 22

[2-butyl-3-[(2'-cyanobiphen-4-yl) -methyl] -6-methylquinazolin-4 (3H) -one]

Quinazolinones prepared as described in Example 1 are alkylated with 4-bromomethyl-2'-cyano-biphenyl. The product is purified by MPLC lova C silica gel column eluting with 20% EtAc / hexanes.

Example 23

[2-butyl-3-[(2'-butoxycarbonyl) biphen-4yl) -methyl] -7-methylquinazolin-4 (3H) -one]

Quinazolinones prepared as described in Example 3 are alkylated with 4-bromomethyl-2'-tert-butoxycarbonylphenyl. The product is purified by effluent chromatography on silica eluting with 20% EtAc / hexanes.

Example 24

[2-butyl-3-[(2 '-(tert-butoxycarbonyl) biphen-4-yl) -methyl] naphtho [2, 3-e] quinazolin-4 (3H) -one]

Quinazolinones prepared as described in Example 4 are alkylated with 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl. The product is purified by MPLC lova B silica gel column eluting with 15% EtAc / hexanes. Yield: 3.6% (Note: low yield due to inseparable byproducts from the starting quinazoline).

Example 25

[2-butyl-3-[(2 '-(tert-butoxycarbonyl) biphen-4yl) -methyl] -6,8-dimethyl quinazolin-4 (3H) -one]

Quinazolinones prepared as described in Example 6 are alkylated with 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl. The product is purified by MPLC lova B silica gel column eluting with 17% EtAc / hexanes.

Example 26

[2-propyl-3-[(2 '-(cyano) biphen-4-yl) -methyl] -6-methylquinazolin-4 (3H) -one]

Quinazolinones prepared as described in Example 2 are alkylated with 4-bromomethyl-2'-cyanobiphenyl. The product is purified by MPLC lova C silica gel column eluting with 30% EtAc / hexanes.

Example 27

[2-Butyl-3-[(2 '-(tert-butoxycarbonyl) bifen-4-yl) -methyl] -5-methylquinazolin-4 (3H) -one]

Quinazolinones prepared as described in Example 5 are alkylated with 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl. The product is purified by MPLC lova B silica gel column eluting with 17% EtAc / hexanes.

Example 28

[6-Isopropyl-2-butyl-3-[(2 '-(N-triphenylmethylterazol-5-yl) biphen-4yl) methyl] quinazolin-4- (3H) one]

Quinazolinones prepared as described in Example 8 are generally alkylated with N-triphenylmethyl-5- [2 (4'-bromomethylbiphenyl)] tetrazol in the same manner as above. The product is purified by MPLC lova silica column to give a colorless oil.

Example 29

[6-Nitro-2-butyl-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4yl) methyl] quinazolin-4 (3H) -one]

Quinazolinones prepared as described in Example 10 are generally alkylated with N-triphenylmethyl-5- [2- (4'-bromomethylbiphenyl)] tetrazol in the same manner as above. The product is purified by effluent chromatography on silica gel starting with 50% CH ₂ Cl ₂ / hexanes, eluting with increasing proportion of EtAc.

Example 30

[2-butyl-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) -biphen-4-yl) methyl] -6-thiomethylquinazolin-4 (3H) -one]

The product of Example 9 is alkylated with N-triphenylmethyl-5- [2- (4'-bromomethylbiphenyl)]-tetrazol according to the method described above. The product is purified by effluent chromatography on silica gel eluting with 20% EtOAC / hexanes.

Example 31

[2-butyl-3-[(4'-fluoro-2 '-(N-triphenylmethyltrazol-5-yl) biphen-4-yl) methyl-6-isopropylquinazolin-4 (3H) -On]

To a solution of 2-butyl-6-isopropylquinazolinone (55.6 mg; 0.228 mmol) (Example 8) in anhydrous DMF (1.5 mL) was added 80% oil dispersion (11.8 mg; 1.5 equiv) of NaH. The reaction mixture is stirred for 30 min under N ₂ . To this was added a solution of (crude) N-triphenyl methyl-5- (4-fluoro-4'-bromomethyl-biphen-2-yl) tetrazole in anhydrous DMF (1.5 ml). Stir under N ₂ for 3 h and then quench with saturated NH 4 Cl solution. The solvent is removed high vacuum, replaced with EtOAc and the insoluble salts are filtered off. The product was purified by effluent chromatography on silica column eluting with hexanes / EtOAc (35: 1) to give the title compound (94.5 mg, 56%). Characteristic peak

Example 32

[2-butyl-6-methyl-3-[(2'-nitrobiphen-4-yl) methyl] -quinazolinone]

To a solution of 2-butyl-6-methylquinazolinone (0.111 g, 0.51 mmol) in dimethylformamide (4.0 ml) was added a 60% oil dispersion of sodium hydride (0.022 g) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere. Stir. After 30 minutes, when H evolution is complete, 4-bromomethyl-2'-nitrobiphenyl is added to the reaction mixture. Stirring is continued for 2 hours at room temperature, then the reaction mixture is partitioned between ethyl acetate and water. The organic layer is extracted, washed with water, brine, dried (MgSO ₄ ), filtered and evaporated. The residual oil was eluted with 25% ethyl acetate-hexanes and purified by silica gel effluent chromatography column to give a colorless oil product (0.129 g, 59%);

Example 33

[3-[(2'-Aminobiphen-4-yl) methyl] -2-butyl-6-methylquinazolin-4 (3H) -one]

10% in a solution of 2-butyl-6-methyl-3-[(2'-nitrobiphen-4-yl) -methyl] quinazolinone (0.127 g, 0.30 mmol) in Example 32 in anhydrous ethanol (15 ml) Pd / powder activated carbon catalyst (0.30 g) is added and the mixture is hydrogenated with a Parr apparatus under 32 psig H atmosphere. After 1 hour, TLC analysis of the reaction mixture (50% ethyl acetate hexane) showed that the reduction was complete. The mixture is filtered, evaporated and then dried in vacuo to give a viscous oil (0.114 g 97%) which is used directly in the next step without further purification.

Example 34

[2-Butyl-6-methyl-3-[(2'-trifluoromethylsulfonamidobiphen-4-yl) -methyl] quinazolin-4 (3H) -one]

To a solution of the product of Example 33 (0.114 g, 0.29 mmol) in dichloromethane (3.0 ml) was added 2,6-di-tert-butyl-4-methylpyridine (0.074 g, 0.36 mmol) and a nitrogen atmosphere at room temperature. The reaction is stirred under. Trifluoromethanesulfonic anhydride (0.101 g, 0.36 mmol) is added at once through a syringe and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is then partitioned between dichloromethane and water and the organic layer is extracted. The organic layer is washed with 1.0N hydrochloric acid followed by water, dried (MgSO ₄ ), filtered and evaporated. The residual oil is purified by silica gel effluent chromatography column, eluting with 25% ethyl acetate-hexane. The purified fractions are evaporated and dried in vacuo to yield a white amorphous solid (0.049 g, 32%).

Example 35

[6-acetoxymethyl-2-butyl-3 [(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4- (3H) -one]

To a solution of the product of Example 14 (0.8 g, 2.9 mmol) in anhydrous DMF (30 ml) at 0 ° C. was added a 0.5 M potassium hexamethyl disilazide solution (6.13 g, 3.0 mmol) in toluene. The reaction mixture is stirred for 30 minutes and then treated with a solution of N-triphenylmethyl-5- [2- (4'-bromomethylbiphenyl)] tetrazole (1.54 g, 3.0 mmol) in DMF (6 ml). . The reaction mixture is stirred for 6 hours while raising the temperature to 25 ° C. The solution is dissolved in EtAc (100 ml) and washed with water (3 × 20 mL) followed by brine (1 × 20 mL) and dried over magnesium sulfate. The mixture was filtered, concentrated in vacuo and the residue was purified by effluent chromatography on silica eluting with 25% EtAc / hexanes to give a white foamy material (0.71 g).

Example 36a

[5-acetoxymethyl-2-butyl-3-[(2 '-(N-triphenylmethyltetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

The product of Example 15 was alkylated with N-triphenylmethyl-5- [2- (4'-bromomethylbiphenyl)] according to the method described in Example 30 to afford the title compound in 57% yield. .

Example 36b

[2-butyl-3- [2 '-(tert-butoxycarbonyl) bifen-4-yl) -methyl] -6-isopropylquinazolin-4- (3H) -one]

2-n-butyl-6-isopropylquinazolin-4-one (prepared as described in Example 8) in a suspension of sodium hydride (0.034 g of 50% oil suspension) in anhydrous DMF (5 ml) (0.2 g, 0.76 mmol) is added and stirred at room temperature for 1.5 hours. In this step, 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl (0.29 g, 0.77 mmol) is added and the mixture is stirred for 18 hours at room temperature. After working up as described in the general procedure for alkylation of quinazolin-4 (3H) -one, the isolated crude product was purified by effluent chromatography on silica gel using methylene chloride containing 1% methanol. The desired compound is obtained as a white amorphous solid (0.23 g, 67%).

From anthranilic acid in a single pot reaction

Alternative method for preparing 2-butyl-3-[(2 '-(N-triphenylmethyl-tetrazol-yl) -biphen-4-yl) methyl] -alkyl-quinazolin-4 (3H) -one

Example 37

[2-butyl-7-chloro-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

Valenoyl chloride (0.24 g, 2.0 mmol) is added to 2-amino-4-chloro-benzoic acid (0.17 g, 1.0 mmol) in pyridine anhydride (1 ml) under N ₂ . The solution is heated for 5 hours. TLC (40% EtAc / hexane) analysis showed a nonpolar intermediate formed. To this solution is added N-triphenylmethyl-5- [2- (4'-aminomethylbiphenyl)] tetazole (0.45 g, 1.0 mmol) and the solution is heated at 120 ° C. overnight. The solution is dissolved in EtOAc (30 ml) and water (10 ml). The organic layer is washed with water (3 × 10 ml), saturated NaHCO ₃ (2 × 10 ml) and saturated NaCl (1 × 10 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was eluted with 20% EtOAc / hexanes and purified by effluent chromatography on silica to give an oil (0.153 g) in 21% yield.

Example 38

[2-butyl-6-ethyl-3 [(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

Purification by flash chromatography eluting with 20% EtOAc / hexanes as described above for Example 37 yields a pale yellow oil in 16% yield.

A further modification of 3-N-alkyl-quinazolin-4- (3H) -one before removing the protecting group

Example 39

[6-Amino-2-butyl-3-[(2 '-(tert-butoxycarbonyl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

2-butyl-3-[(2 '-(tert-butoxycarbonyl) biphen-4-yl) -methyl] -6-nitroquinazolin-3 (1H) -one (Example 21) (0.11 g , 0.21 mmol) is suspended in MeOH (7.5 ml) and hydrogenated to 10% Pd / C (55 mg) under atmospheric H blanket. After 1 hour, the reaction mixture is filtered through celite and the filtrate is concentrated in vacuo. The residue was eluted with 50% EtOAc / hexanes and purified by effluent chromatography on silica gel to give a white foamy material (69 g, 0.14 mmol) in 67% yield.

Example 40

[6-Amino-2-butyl-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) bifen-4-yl) methyl] quinazolin-4 (3H) -one]

The 6-nitroquinazolinone (3.2 g, 4.4 mmol) solution from Example 28 in EtOAc (100 ml) is hydrogenated overnight under atmospheric pressure in the presence of 10% Pd / C (0.5 g). The solution is filtered through celite and the celite is washed with CH ₂ Cl ₂ to remove the yellow product. The filtrate was concentrated in vacuo to yield a pale yellow solid (3.0 g). The substance is no longer purified. Yield is 98%.

Example 41

[6-amino-2-propyl-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

The product of Example 32 is hydrogenated as described in Example 40. The product is purified by effluent chromatography on silica gel eluting with 7% acetone / CH ₂ Cl ₂ to give a pale yellow solid.

Example 42

[6-acetamide-2-butyl-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

To a solution of aminoquinazolinone (0.12 g, 0.17 mmol) from Example 40 in CH ₂ Cl ₂ (2 ml) is added triethylamine (33 g, 0.32 mmol) followed by dimethylaminopyridine (10 mg). The reaction mixture is cooled to 0 ° C. and treated with acetyl chloride (14 g, 0.19 mmol). The solution is allowed to warm to room temperature and additional 0.3 equivalents of acetyl crawlide are added and the mixture is stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by effluent chromatography on silica gel, eluting with 50% EtOAc / hexanes, gradually increasing to a CH ₂ Cl ₂ concentration of 10% to give the title compound (0.073 g) in 57% yield. .

Example 43

[2-butyl-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) -biphen-4-yl) methyl] -6-valeroylamido-quinazolin-4 (3H )-On]

The product of Example 40 is acylated with valeroyl chloride in the same manner as described in Example 42. The product is eluted with 30% EtOAc / hexanes and purified by effluent chromatography on silica gel by increasing the concentration of EtOAc to 50% to give an oil.

Example 44

[2-butyl-6- (N-carbenzyloxy) amino-3-[(2 '-(N-triphenylmethyl-methyl-tetrazol-5-yl) biphen-4-yl) -methyl] quinazoline -4 (3H) -on]

To nitrogen was added 6-aminoquinazolino (69 mg, 0.1 mmol) from Example 40 at 0 ° C. to 80% NaH (4 g, 0.12 mmol) suspension in oil in anhydrous DMF (1 mL). A light blue solution is formed. After 0.5 h benzylchloroformate (18.8 mg, 0.1 mmol) was added via syringe. The blue color disappears quickly and the reaction mixture is stirred for 3 hours while warming to room temperature. The reaction mixture is concentrated in vacuo and the residue is dissolved in EtOAc (25 ml) and water (5 ml). The steam is extracted with EtOAc (2 × 5 ml) and the combined organic phases are washed with water (1 × 5 ml) and brine (1 × 5 ml) and then dried over magnesium sulfate. The mixture was filtered, concentrated in vacuo, and the residue was purified by effluent chromatography on silica gel, eluting with 30% EtOAc / hexanes to yield 62% (51.7 g, 0.62 mmol) of the compound of Example 26.

Example 45

[6- (N-isopropylcarbomoyl) amino-2-propyl-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl] -quinazolin- 4 (3H) -on]

The product of Example 41 is converted to the title compound in the same manner as described in Example 51. The product is eluted with 65% EtOAc / hexanes and purified by MPLC on silica gel to give a colorless oil.

Example 46

[2-butyl-6- (N-carbenzyloxy-N-methyl) amino-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl] amino Quinazolin-4 (3H) -one]

To a 80% NaH (20 mg, 0.65 mmol) suspension in mineral oil in anhydrous DMF (2 ml) is added the solution of Example 44 (0.49 g, 0.59 mmol) in DMF (4 ml) at 0 ° C. under nitrogen. When NaH is consumed a blue solution is formed. The reaction mixture is stirred for 90 minutes and methyl iodide (0.04 ml, 0.6 mmol) is added. The ice bath is removed and the reaction mixture is stirred for an additional 45 minutes. Water (1 ml) is added to the reaction mixture and DMF is removed in vacuo. The residue is dissolved in EtOAc (5 ml) and the organic layer is washed with water (2 × 20 ml) and brine (1 × 20 ml). The mixture is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was eluted with 30% EtOAc / hexanes and purified by effluent chromatography on silica gel to give an orange solid (0.44 g, 0.52 mmol).

Example 47

[2-propyl-6- (N-methyl-N-isobutyloxycarbonyl) amino-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl ] Quinazolin-4 (3H) -one]

To a 80% NaH (0.7 mg, 0.32 mmol) suspension in oil in anhydrous DMF (0.5 ml) is added a solution of Example 41 (0.2 g, 0.29 mmol) in DMF (0.5 ml) at 0 ° C. The orange solution is stirred for 30 minutes and then treated with isobutyl chloroformate (40 mg, 0.29 mmol). After 1 hour, a 1M hexamethyl disilizide solution (0.37 ml) in THF is added dropwise to the reaction mixture. A red solution is formed, to which iodomethane (0.58 mg, 0.41 mmol) is added. The reaction mixture is stirred overnight and concentrated in vacuo. The residue is dissolved in EtOAc (20 ml), washed with water (2 x 5 ml), then brine (1 x 5 ml) and dried over magnesium sulfate. The solution is filtered and concentrated in vacuo. The residue was purified by MPLC on silica gel eluting with 30% EtOAc in hexane to give 0.132 g of a colorless oil (yield: 56%).

Example 48a

[2-propyl-6- (N-ethyl-N-isobutyloxycarbonyl) amino-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl ] Quinazolin-4 (3H) -one]

The product of Example 41 is acylated with isobutyl chloroformate and then alkylated with iodoethane by the method described in Example 47 to afford the title compound.

Example 48b

[6- (N-butyl-N-isobutyloxycarbonyl) -amino-2-propyl-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) -biphen-4-yl ) -Methyl] quinazolin-4 (3H) -one]

The product of Example 41 is acylated with isobutyl chloroformate and then alkylated with butyl iodide by the method described in Example 47 to give the title compound (yield: 71%).

Example 49

[6- (N-benzyl) amino-2-butyl-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -On]

To the amine of Example 40 (100 mg, 0.14 mmol) in EtOH (2 ml) was added benzaldehyde (16 mg, 0.15 mmol). The reaction mixture is heated to 60 ° C. for 1 hour, cooled to 0 ° C. and then treated with 1M NaCNBH ₃ solution (0.29 ml, 0.29 mmol) in THF. The reaction mixture is stirred overnight, concentrated in vacuo, and the residue is partitioned between EtOAc (25 ml) and water (15 ml). The layers are separated and the organic layer is washed with brine (1 × 25 ml) and then dried over magnesium sulfate. The mixture is filtered, concentrated in vacuo and the residue is purified by effluent chromatography on silica gel, eluting with 25% EtOAc / hexanes to give 45 mg (0.06 mmol) of yellow foamy material.

Example 50

[2-butyl-6- (N, N-dimethyl) amino-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 ( 3H) -on]

Promalin (300 mg) is added to nitroquinazolinone (100 mg, 0.138. Mmol) in Example 29 in EtAc (1 ml) and MeOH (1 ml), followed by 10% Pd / C (25 mg). The mixture is stirred overnight at atmospheric pressure under H. The reaction mixture is filtered and concentrated in vacuo. The residue is purified by effluent chromatography by eluting with 30% EtOAc / hexanes in silica gel.

Example 51

[2-butyl-6- (N-isopropylcarbamoyl) amino-3-[(2 '-(N-triphenylmethyl-tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -on]

To isopropyl isocyanate (12.7 mg, 0.15 mmol) is added to a solution of aminoquinazolinone (0.069 g, 0.1 mmol) from Example 40 in CH ₂ Cl ₂ (1 ml). The reaction mixture is stirred for 3 days. The mixture is washed with EtOAc (20 ml), water (2 x 5 ml) and brine (1 x 5 ml) and dried over magnesium sulfate. The mixture was filtered, concentrated in vacuo and the residue was eluted with 50% EtOAc / hexanes and purified by MPLC on silica lova B column to give an oil (59.5 mg, 0.0.7 mmol) (yield: 76%).

Example 52

[6-acetamide-2-butyl-3-[(2 '-(tert-butoxycarbonyl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

To the product of Example 39 (20 mg) in CH ₂ Cl ₂ (0.75 ml) is added acetic anhydride (4.3 μl) at room temperature. After 6 hours, acetic anhydride (2 μl) is further added to the reaction mixture. The solution is stirred for 7 days, diluted with EtOAc (10 ml), then washed with water (3 × 5 ml), brine (1 × 5 ml) and dried over magnesium sulfate. The solution is filtered and concentrated in vacuo to give 22 mg of a white solid (yield: 100%). Attempts to dissolve in EtOAc and CH ₂ Cl ₂ for chromatography failed because of its insolubility.

[Synthesis of 2-butyl-3-[(2 '-(carboxy) biphen-4-yl) methyl] -alkyl-quinazolin-4 (3H) -one]

The general procedure for preparing carboxylic acids from tert-butyl esters is as follows:

Trifluoroacetic acid (0.5 ml) is added to ester (1 mmol) in anhydrous CH ₂ Cl ₂ (1 ml) at room temperature. The solution is stirred overnight under N ₂ and concentrated in vacuo. The reaction product is dissolved in a mixture of CH ₂ Cl ₂ (0.5 ml) and toluene (3 ml) and the residue is reconcentrated in vacuo. The residue is vacuum dried overnight. The impurities are removed by an effluent chromatography.

Example 53

[6-acetamide-2-butyl-3-[(2 '-(carboxyl) biphen-4-yl) methyl] -quinazolin-4 (3H) -one]

The product of Example 52 is deprotected according to the general method described above. Elution with 5: 95: 1 MeOH: CH ₂ Cl ₂ : HOAc purified by effluent chromatography to give a white solid.

Example 54

[6-amino-2-butyl-3-[(2 '-(carboxy) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

The product of Example 39 is deprotected according to the general method described above. Elution with 60: 40: 1 EtAc: hexanes: acetic acid on silica gel purifies by effluent chromatography. The product is very insoluble and a white solid is obtained when concentrated.

Example 55

[2-butyl-3-[(2 '-(carboxyl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

The product of Example 17 was deprotected according to the general procedure described above. The crude is eluted with 1: 1: 38: 60 acetic acid / MeOH / hexanes / methylene chloride and purified by effluent chromatography.

Example 56

[2-butyl-3-[(2 '-(carboxyl) biphen-4-yl) methyl] -5-methylquinazolin-4 (3H) -one]

The product of Example 27 is deprotected according to the general procedure described above. The crude concentrated reaction mixture was homogeneous by TLC and NMR analysis.

Example 57

[2-butyl-3-[(2 '-(carboxy) biphen-4-yl) methyl] -naphtho [2,3-e] quinazolin-4 (3H) -one]

The product of Example 24 is deprotected according to the general method described above. TLC and NMR analysis of the crude concentrated reaction mixture showed homogeneity.

Example 58

[2-butyl-3-[(2 '-(carboxy) biphen-4-yl) methyl] -7-methylquinazolin-4 (3H) -one]

The product of Example 23 is deprotected according to the general procedure described above. The product is purified by effluent chromatography on silica gel eluting with 40% EtOAc / hexane / 1% acetic acid.

Example 59

[2-butyl-3-[(2 '-(carboxy) biphen-4-yl) methyl] -8-methylquinazolin-4 (3H) -one]

The product of Example 19 is deprotected according to the general procedure described above. The product is purified by effluent chromatography, eluting with 25% EtOAc / 75% hexane / 1% acetic acid.

Example 60

[2-butyl-3-[(2 '-(carboxy) biphen-4-yl) methyl] -6-methylquinazolin-4 (3H) -one]

The product of Example 20 is deprotected according to the general procedure described above. The product is purified by effluent chromatography by eluting with 30% EtOAc / 70% hexane / 1% acetic acid on silica gel.

Example 61

[2-butyl-3-[(2 '-(carboxy) biphen-4-yl) methyl] -6-nitroquinazolin-4 (3H) -one]

The product of Example 21 is demolded according to the general procedure described above. The product is purified by effluent chromatography, eluting with 70: 30: 1 EtOAc: hexane: acetic acid on silica gel.

Example 62a

[2-butyl-3-[(2 '-(carboxy) biphen-4-yl) methyl] -6,8-dimethylquinazolin-4 (3H) -one]

The product of Example 25 is deprotected according to the general procedure described above. Elution with 30% EtOAc / hexane / 1% acetic acid is purified by effluent chromatography on silica gel.

Alternative Method for Preparing Carboxylic Acid from Tert-Butyl Ester

Example 62b

[2-butyl-3-[(2 '-(carboxy) biphen-4-yl) -methyl] -6-isopropylquinazolin-4 (3H) -one]

2-n-butyl-3-[(2 '-(tert-part) from Example 36b in a mixture of methylene chloride (3 ml) containing anisole (0.05 ml) and trifluoroacetic anhydride (3 ml) The oxy-carbonyl) biphen-4-yl) -methyl] -6-isopropylquinazolin-4 (3H) -one (0.198 g, 044. mmol) solution is stirred at room temperature for 4 hours. The solvent is then removed under reduced pressure and the residue is triturated with anhydrous ether to give a solid product which is then collected by filtration and dried in vacuo with NaOH and P ₂ O ₅ to afford the desired product as a monotrifluoroacetate salt.

[Synthesis of 2-butyl-3 [(2 '-(tetrazol-5-yl) bifen-4-yl) methyl] quinazolin-4- (3H) -one from trityl protected intermediate]

Example 63

[2-butyl-3-ethyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

The protected tetaazole (0.116 g, 0.165 mmol) from Example 38 was stirred with 1 ml of a mixture of 1: 1: 1 HOAc: THF: H ₂ O at 90 ° C. for 2 hours and then at room temperature for 4 hours. Stir. The reaction mixture is concentrated in vacuo and the residue is purified by effluent chromatography on silica gel eluting with 40: 59: 1 EtOAc: hexanes: HOAc. Recover white powder (53.4 mg).

Example 64

[2-Butyl-7-chloro-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

Prepared as in Example 63 from the product of Example 37. Elution with 40: 59: 1 EtOAc: hexanes: HOAc purified by effluent chromatography on silica gel to give a white powder.

Example 65

[2-butyl-6-isopropyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

Prepared as in Example 63 from the product of Example 28. Elution with 40: 59: 1 EtOAc: hexanes: HOAc purified by effluent chromatography on silica gel to give a white powder.

Example 66

[6-acetoxymethyl-2-butyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

The product of Example 35 is deprotected as in the method of Example 63. The product is eluted with 50: 49: 1 EtOAc: hexane: acetic acid and purified by effluent chromatography on silica gel to give a white powder (92% yield).

Example 67

[5-acetoxymethyl-2-butyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

The product of Example 36 is deprotected as in the method of Example 63. The product was purified by effluent chromatography on silica gel eluting with 50: 50: 1 EtOAc: hexane: acetic acid to give a white powder (78% yield).

Example 68

[2-butyl-6-nitro-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

The product of Example 29 is deprotected as in the method of Example 63. The product was purified by effluent chromatography on silica gel eluting with 50: 49: 1 EtOAc: hexane: acetic acid to give a white powder (98% yield).

Example 69

[6-Amino-2-butyl-3- [2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

The product of Example 40 is deprotected as in the method of Example 63. The product is purified by effluent chromatography on silica gel eluting with 95: 5: 0.1 CHCI ₃ : MeOH: NH ₄ OH to give a white powder (68% yield).

Example 70

[6- (N-benzyl) amino-2-butyl-3- [2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

The product of Example 49 is deprotected as in the method of Example 63. The product is purified by effluent chromatography on silica gel eluting with 5: 95: 0.01 MeOH: CHCI ₃ : NH ₄ OH to give a white powder. This material is purified by MPLC on silica lova A column, eluting with 50: 50: 1 EtOAc: hexanes: acetic acid.

Example 71

[2-butyl-6- (N, N-dimethyl) amino-3- [2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

The product of Example 50 is deprotected as in the method of Example 63. The product was purified by effluent chromatography on silica gel eluting with 5% MeOH / CHCI ₃ (95% yield).

[Another way to deprotect the trityl group]

Example 72

[6-Acetamido-2-butyl-3- [2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

Four drops of concentrated HCI are added dropwise to the solution from Example 42 (0.073 g, 0.099 mol) in MeOH (2 ml). The reaction mixture is stirred for 5 minutes and then made basic by addition of concentrated NH ₄ OH. Acetic acid is added to adjust the pH of the solution to 5.0. The reaction mixture is concentrated in vacuo and the residue is dissolved in EtoAc (20 ml). The solution is washed with radish (2 × 5 ml) and brine (1 × 5 ml) and dried (MgSO ₄ ). The mixture is filtered and then concentrated in vacuo. The crude product is extremely insoluble, so it is finally purified by polishing with CHCI ₃ , EtOAc and hexanes to give an off-white solid (65% yield).

Example 73

[2-butyl-3- [2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] -6-valeroylamidoquinazolin-4 (3H) -one]

The product of Example 43 is deprotected by the method described in Example 72. The crude product is purified by grinding with a mixture of EtOAc hexanes to give a powder (78% yield).

Example 74

[2-butyl-6-[(N-carbenzyloxy-N-methyl) amino-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H )-On]

The product of Example 46 is deprotected by the method described in Example 72. The product was eluted with 40: 59: 1 EtOAc: hexanes: acetic acid and purified by MPLC on Silica Rova A comum to yield a white foamy material in 87% yield.

Example 75

[2-butyl-6- (N-carbenzyloxy) amino-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

The product of Example 45 is deprotected by the method described in Example 72. The product is eluted with 40: 59: 1 EcOAc: hexanes: acetic acid and purified by MPLC on silica lova A column to give a white solid in 55% yield.

Example 76

[2-butyl-6- (N-isopropylcarbamoyl) amino-3-[(2'-tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

The product of Example 51 is deprotected according to the procedure of Example 72. The product is purified by grinding with EtOAc and hexanes.

Example 77

[2-butyl-3-([2 '-(tetrazol-5-yl) biphen-4-yl) methyl] -6-thiomethylquinazolin-4 (3H) -one]

The product of Example 30 is deprotected in the same manner as described in Example 72. The crude product is purified by effluent chromatography on silica gel eluting with 50: 49: 1 EtOAc: hexane: acetic acid to yield 83% yield.

Example 78

[6- (N-isopropylcarbamoyl) amino-2-propyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4- (3H) -one ]

The product of Example 45 is deprotected by the method described in Example 72. The product is purified by grinding with EtOAc to give a white solid in 62% yield.

Example 79

[6- (N-methyl-N-isobutyloxycarbonyl) amino-2-propyl-3- [2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H )-On]

The product of Example 47 is deprotected by the method described in Example 72. The product was purified by effluent chromatography on silica gel eluting with 50% EtOAc in hexane + 1% acetic acid to give a white solid.

Example 80a

[6- (N-ethyl-N-isobutyloxycarbonyl) amino-2-propyl-3- [2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H )-On]

The product of Example 48a is deprotected by the procedure described in Example 72. The product is purified by effluent chromatography on silica gel eluting with 50% EtOAc / hexanes + 1% acetic acid.

Example 80b

[6- (N-butyl-N-isobutyloxycarbonyl) -amino-2-propyl-3- [2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 ( 3H) -on]

The product of Example 48b is deprotected by the method described in Example 72. The product is purified by effluent chromatography on silica gel eluting with 40: 60: 1 EtOAc: hexane: acetic acid to give a white solid in 69% yield.

Example 81

[2-butyl-6- (N-methyl-N-isobutyloxycarbonyl) amino-3- [2 '-(tetrazol-5-yl) -biphen-4-yl) methyl] quinazolin-4 ( 3H) -on]

The product of Example 95 is deprotected by the method described in Example 72. The product is purified by effluent chromatography on silica gel eluting with 50% EtOAc / hexanes + 1% acetic acid to give a white solid.

Example 82

[2-Butyl-3- (4'-fluoro-2 '-(tetrazol-5-yl) biphen-4-yl) -methyl-6-isopropylquinazolin-4 (3H) -one]

2-butyl-3- (4'fluoro-2 '-(N-triphenyl-methyltetrazol-5-yl) biphen-4-yl) methyl-6-iso from Me 33 in MeOH (4m) Add 9 N HCI (10 drops) to the propylquinazolinone solution. Stir overnight (94.5 mg; 0.128 mol) to the reaction. After about 15 hours, MeOH is removed under vacuum. The product was purified by polishing with Et ₂ O to afford the title compound (54.2 mg, 80%).

[Synthesis of 2-butyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one from nitrile]

The general procedure for converting biphenyl nitrile to tetrazole is as follows:

Trimethylstanyl azide (see above) was added to a nitrile (0.28 mmol) solution dissolved in anhydrous toluene (2 mL). The reaction mixture is refluxed overnight, at which time additional azide (0.56 mmol) is added and the reaction mixture is refluxed for an additional 12 hours. The resulting suspension was suspended in EtOAc (50 mL), washed with saturated NH ₄ CI (3 × 10 mL) and dried (MgSO ₄ ). The solution is vacuum filtered and concentrated. Purification and spectral data are shown below.

Example 83

[2-butyl-6-methyl-[(2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

The product of Example 22 is subjected to the general overcoagulation above. The residue was eluted with 60% EtOAc / hexane / 1% acetic acid and purified by effluent chromatography on silica gel to give 0.08 mmol of pure tetrazole in 32% yield.

Example 84

[2-butyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] -quinazolin-4 (3H) -one]

The product of Example 18 is treated in the general manner as above. The residue was eluted with an eluent of acetic acid: EtOAc: hexane 1:40:59 and purified by MPLC on silica gel. The recovered product [Rf = 0.27 (acetic acid: EtOAc: hexane = 1: 39: 60)] was eluted with 75:25 acetonitrile: water / 0.01% TFA and purified by HPLC on a C8 reversed phase column to give 26% yield. The product is obtained as a white foamy material.

Example 85

[6-Methyl-2-propyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

The product of Example 26 is treated in the general manner above. Crude tetrazole is purified in 13% yield in the same manner as in 2-butyl above.

[Another variation of antagonist]

Example 86

[2-butyl-6-hydroxymethyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

The solution of Example 66 (0.2 g, 0.38 mmol) was dissolved in MeOH (5 mL), treated with 1N NaOH (1 mL, 1.0 mmol) and stirred overnight. The resulting solution is extracted with EtOAc (3 × 10 mL). The organic layer is washed with water (2 × 5 mL) and brine (1 × 5 mL) and dried (MgSO ₄ ). The mixture was vacuum filtered, dried, and the residue was eluted with 80: 19: 1 EtOACc: hexane: acetic acid and purified by effluent chromatography on silica gel to yield 0.17 g (0.36 g) of white foamy material in 93% yield. mmol).

Example 87

[2-butyl-5-hydroxymethyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

To the solution of Example 31 (0.2 g, 273 mmol) in MeOH (8 mL) was added 20 drops of concentrated HCI. The reaction mixture is stirred overnight, then the pH is adjusted to 6.0. MeOH was removed in vacuo, the residue was triturated with EtOAc (3 mL) and dried to yield 90 mg (1.9 mmol) of white powder.

Example 88

[2-butyl-6-carboxy-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

To the solution of Example 86 (115 mg, 0.25 mmol) in CH ₂ CI ₂ (6 mL) was added MnO ₂ (600 mg), followed by addition of 3 ′ molecular sieve (200 mg). The reaction mixture is stirred for 12 hours and then filtered through celite. Celite is washed with CH ₂ CI ₂ (20 mL) and the combined filtrates are concentrated in vacuo to give a white foamy material (65 mg). The crude aldehyde intermediate (31 mg, 0.067 mmol) is suspended in 3-tert-BuOH (0.4 mL) and treated with 5% NaH ₂ PO ₄ (260 μ1) and 0.5N KMnO ₄ solution (780 μ1) in water. After 1 h, the reaction mixture is concentrated in vacuo and the residue is partitioned between water (30 mL) and 60 mL EtOAc. The aqueous layer is extracted with EtOAc (2 × 10 mL) and the combined organic layers are washed with brine (1 × 10 mL) and then dried (MgSO ₄ ). No product is detected in this organic layer. The aqueous layer is acidified to pH 1.0 with concentrated HCI and extracted with EtOAc (3 × 50 mL). The combined organic layers are washed with water (2 × 15 mL) and brine (1 × 15 mL) and dried (MgSO ₄ ). The solution is dried (MgSO ₄ ), filtered and concentrated in vacuo to yield 20 mg of a color solid in 59% yield.

Example 89

[2-butyl-5-carboxy-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

To the product of Example 87 (50 mg, 0.1 mmol) suspended in CH ₂ CI ₂ (3 mL) is added activated MnO ₂ (500 mg) and one spatula portion of activated 3 ′ molecular sieve. The mixture is stirred vigorously under N ₂ overnight. Initial experiments showed that the aldehydes produced were very insoluble and prone to attachment to MnO ₂ . The reaction mixture is concentrated in vacuo and the crude mixture is treated with tert-BuOH (0.6 mL), 5% aqueous NaH ₂ PO ₄ (0.42 mL) and 0.5N KMNO ₄ (0.25 mL). The solvent is removed in vacuo and the residue is suspended in a mixture of EtOAc (40 mL) and water (40 mL). The mixture is then filtered to remove MnO ₂ and the solid residue is washed with water and EtOAc. The resulting suspension is treated with 1N NaOH (5 mL) to make the aqueous layer basic and the suspension is removed. The aqueous layer is extracted with EtOAc (3 × 50 mL) and the combined organic extracts of the acidified solution are washed with brine (1 × 50 mL) and then dried (MgSO ₄ ). The mixture was vacuum filtered and concentrated to yield 35.5 mg (0.07 mmol) of solid in 69% yield.

Example 90

[2-butyl-6-carbomethoxy-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

To a suspension of the product of Example 86 (65 mg, 0.14 mmol) in CH ₂ CI ₂ (3 mL) was added MnO ₂ (650 mg) and activated 3 ′ molecular sieve powder (200 mg). The reaction mixture was stirred for 3 hours and analyzed by TLC (EtOAc: hexanes: acetic acid is 70: 30: 1) showed complete conversion to a low polar aldehyde intermediate. The reaction mixture is concentrated in vacuo and the residue suspended in MeOH (3 mL). To the suspension is added 35 mg NaCN (0.7 mmol) and 12 mg acetic acid (0.21 mmol). The reaction mixture is stirred overnight and then filtered through celite. The solid residue is washed with MeOH (20 mL). The filtrate is concentrated in vacuo and the residue is redissolved in EtOAc (65 mL). The solution is washed with water (3 × 40 mL) and brine (1 × 40 mL) and dried (MgSO ₄ ). The mixture was vacuum filtered and dried to give 29 mg of oil. The product was purified by effluent chromatography on silica gel eluting with EtOAc: hexane: acetic acid 50: 49: 1 to give 19 mg (0.04 mmol) of white foamy material in 27% yield.

Example 91

[2-butyl-5-carbomethoxy-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) -methyl] quinazolin-4 (3H) -one]

The product of Example 87 is treated as described in Example 90 to yield a crude ester. The product is eluted with EtOAc: hexane: acetic acid 60: 40: 1 and purified by MPLC on silica gel Lova A column to give a white foamy material in 38% yield.

Example 92

[2-butyl-6- (N-methyl) amino-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

The solution of Example 46 (0.23 g, 0.27 mmol) in MeOH (50 mL) in the presence of 10% Pd / C (50 mg) is hydrogenated at atmospheric pressure. When the starting material is exhausted, the reaction mixture is filtered through celite and the filtrate is concentrated in vacuo to yield 0.19 g of a colored foamy material. This product was purified by effluent chromatography on silica gel eluting with 40% EtOAc / hexanes to give 2-butyl-6- (N-methyl) amino-3-[(2 '-(N-triphenylmethyl-tetrazole). 71 mg (0.1 mmol) of -5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one are obtained. This column is further eluted with EtOAc: hexanes: acetic acid 70: 30: 1 to give 43 mg of compound free of crude trityl. The chromatographed silica gel is washed with EtOAc: hexane: acetic acid 70: 30: 1 to give additional small amount of product after filtration. The combined trityl-free product was eluted with EtOAc: hexane: acetic acid 70: 30: 1 and purified by effluent chromatography on silica gel to give 2-n-butyl-3-[(2'-) in a total yield of 66%. 39 mg (0.08 mmol) of (tetrazol-5-yl) biphen-4-yl) methyl] -6- (N-methyl) aminoquinazolin-4- (3H) -one are obtained. The tritylated material can be deprotected as in Example 54 to yield additional amounts of the desired product.

Example 93

[2-butyl-6- (methylsulfonyl) -3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one]

At room temperature, 30% H peroxide (5 mL) is added to a deprotected quinazolinone (0.05 g, 0.11 mmol) solution from Example 77 in acetic acid (3 mL). The reaction mixture is stirred overnight and concentrated in vacuo. The residue is purified by effluent chromatography on silica gel eluting with EtOAc: hexane: acetic acid 65: 34: 1. The product is dissolved in toluene, acetic acid is removed by azeotropic distillation and concentrated in vacuo to yield 32 mg (0.06 mmol) of white powder in 62% yield.

Example 94

[2-butyl-6- (methylsulfinyl) -3-[(2 '-(tetrazol-5-yl) -biphen-4-yl) methyl] quinazolin-4 (3H) -one]

To a deprotected quinazolinone (43.7 mg, 0.1 mmol) solution from Example 77 in acetic acid (1 mL) is added a 30% H ₂ O ₂ solution (12.4 mg, 0.11 mmol) in water. After stirring overnight, TLC (50: 30: 19: 1 EtOAc: hexane: MeOH: acetic acid) analysis showed complete reaction. Further H ₂ O ₂ solution (12.4 mg) is added and after 2 hours complete conversion to a more polar product. The reaction mixture was concentrated in vacuo and the residue was eluted with EtOAc: hexane: MeOH: acetic acid 50: 30: 19: 1 and purified by effluent chromatography on silica gel to yield 27 mg (0.05 mmol) of a white solid (50%). do.

Example 95

[2-butyl-6- (N-methyl-N-isobutyloxycarbonyl) amino-3-[(2 '-(N-triphenylmethyltetrazol-5-yl) -biphen-4-yl) methyl ] Quinazolin-4 (3H) -one]

Intermediate product 2-n-butyl-6- (N-methyl-amino) -3- [2 '-(N-triphenylmethyl-tetrazol-5-yl) -biphen-4-yl) methyl of Example 92 ] -Quinazolin-4 (3H) -one is converted to the title compound according to the following method. Triethylamine (24.8 mg, 0.244 mmol) was added to a methyl amine (0.08 g, 0.011 mmol) solution in anhydrous DMF (1 mL), followed by addition of isobutylchloroformate (33 mg, 0.24 mmol). The reaction mixture is stirred over 48 hours and diluted with 25 ml of EtOAc. The solution is washed with water (2 × 10 mL) and brine (1 × 10 mL) and dried (MgSO ₄ ). The solution was filtered and concentrated in vacuo to elute the residue with 40% EtOAc / hexanes and purified by MPLC on silica gel to give 0.052 g of a colorless oil.

Example 96

[2-Butyl-3-[(2 '-(N-benzenesulfonyl) carboxamidobiphen-4-yl) -methyl] -6-isopropylquinazolin-4 (3H) -one]

The carboxylic acid (0.05 g, 0.088 mmol) obtained in Example 62b was dissolved in anhydrous THF (1 mL) and 1,1 'carbonyl-diimidazole (0.030 g, 0.18 mmol) was added to the solution. The mixture is refluxed for 4 hours and then cooled to room temperature. Benzenesulfonamide (0.031 g, 0.19 mmol) and DBU (0.029 g) are then added to the reaction and the mixture is refluxed for 7 hours. The reaction is then concentrated in vacuo and the residue is treated with 5% aqueous citric acid (5 mL) and then extracted with ethyl acetate (3 x 15 mL). The combined organic layers are washed with brine and then dried over anhydrous sodium sulfate. After removal of the solvent, the obtained crude product is purified by effluent chromatography on silica gel using 2% methanol in methylene chloride to afford the title compound.

Preparation of 1,2-Substituted Quinazolin-4 (1H) -ones

Example 97

[N-Valeroyl-2-aminobenzonitril]

Valeryl chloride (562 mg, 4.66 mmol) in 2-aminobenzonitrile (500 mg, 4.23 mmol), triethylamine (514 mg, 5.08 mmol) and DMAP (50 mg, 041 mmol) in CH ₂ CI ₂ (6 mL) at 0 ° C. ) Over 1 minute. The mixture is allowed to warm to room temperature and stirred for 20 minutes. The mixture is then diluted with water and brine and extracted three times with ether. The combined organics are dried (MgSO ₄ ), the solvent is removed in vacuo, eluted with 20% ethylacetate in hexane and purified by effluent chromatography on silica to afford the title compound.

Example 98

[N-Valeroyl-N-[(2 '-(tert-butoxycarbonyl) biphen-4-yl) -methyl] -2-aminobenzonitrile]

Product of Example 97 (146 mg, 0.72 mmol), 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl (250 mg, 0.72 mmol) and NaI (119 mg, 0.79 mmol) in DMF (4 mL) at room temperature To the solution is added 60% NaH (46 mg) dispersion in oil (1.15 mmol). After 45 minutes the mixture is diluted with water and brine and then extracted three times with ether. The combined organics are dried (MgSO ₄ ), the solvent is removed in vacuo, then eluted with 20% ethyl acetate in hexanes and purified by MPLC on silica.

Example 99

[2-butyl-1-[(2 '-(carboxy) biphen-4-yl) methyl] quinazolin-4 (1H) -one]

Purified N-valeroyl-N-[(2 '-(tert-butoxycarbonyl) biphen-4-yl) methyl] -2-aminobenzonitrile (Example 98) in methanol (4 mL) at room temperature To the solution is added 30% H ₂ O ₂ (245 mL) and 3.0 N NaOH (720 mL). The mixture is heated to reflux for 1 hour. Additional 30% H ₂ O ₂ (245 mL) is added and the mixture is refluxed for 45 more minutes. The solution is diluted with brine and then extracted three times with ether. The combined organics were dried (MgSO ₄ ), the solvent was removed in vacuo, eluted with 25% ethyl acetate in methylene chloride and effluent chromatography on silica to give a white solid [Rf = 0.13 (25% ethyl acetate in methylene chloride)). ] Is obtained. The solid is stirred in CH ₂ CI ₂ (4 mL) and TFA (4 mL) over 4 hours. The volatiles are removed in vacuo and the crude is eluted with 1: 4: 95 acetic acid / methanol / methylene chloride to give an effluent chromatography to give a white crystalline solid.

Example 100

Conventional Pharmaceutical Compositions Containing Compounds of the Invention

[A. Dry Filled Capsules with 50mg of Active Ingredient Per Capsule]

2-butyl-6-isopropyl3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one as No. 60 powder, followed by lactose Oz and magnesium stearate can be passed through a No. 60 blotting colth to powder. The combined ingredients can then be mixed for about 10 minutes and then filled into No. 1 dry gelatin capsul.

[B. refine]

Typical tablets are 2-butyl-6-isopropyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] -quinazolin-4 (3H) -one (25 mg), Contains pregelatinized component USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).

[C. Compound tablets;

Typical combination tablets contain a diuretic such as, for example, hydrochlorothiazide, and 2-butyl-6-isopropyl-3- (2 '-(tetrazol-5-yl) biphen-4-yl) methyl] Quinazolin-4 (3H) -one (50 mg), pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).

[D. Suppository]

Suppository formulations for conventional rectal administration include 2-butyl-6-isopropyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one ( 0.08 to 1.0 mg), disodium calcium edetate (0.25 to 0.5 mg) and polyethylene glycol (755 to 1600 mg). Other suppository formulations, for example, replace disodium calcium edate with butylated hydroxytoluene (0.04-0.08 mg) and polyethylene glycol with hydrogenated vegetable oils (e.g., Suppocirel L, Wecobee FS, Wecobee M, Witepsols It can be prepared by replacing with). These suppository formulations may also contain other active ingredients such as, for example, another blood pressure potentiating and / or diuretic and / or angiotensin converting enzyme and / or calcium channel blocker as described in C, above, It may be contained in an effective amount.

[E. Injection]

Conventional injection formulations are 2-butyl-6-isopropyl-3-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] quinazolin-4 (3H) -one sodium phosphate dibasic Anhydride (11.4 mg), benzyl alcohol (0.01 mL) and distilled water for injection (1.0 mL) are included. Such injection formulations may also contain pharmaceutically effective amounts of other active ingredients, such as another blood pressure lowering agent and / or diuretic and / or angiotensin converting enzyme inhibitor and / or calcium channel blocker.

Claims (4)

Compounds of formula (I) and pharmaceutically acceptable salts thereof.

In formula (I) above, L is linked to J or K to form an aromatic ring as defined below, J is -C (= M)-or J and L are linked together to R ^7a , R ^{7b ,} R ^8a and R ^8b of a carbon number of 6 to form an aromatic ring, and J-stage and only one -C (= M) of K is substituted by - a, K is -C (= M) - or, with the K and L Linked to form an aromatic ring of 6 carbon atoms substituted with R ^7a , R ^7b , R ^8a , R ^8b , provided that only one of J and K is -C (= M)-, M is oxygen or NR ²² , and R ¹ is (a) -CO ₂ R ⁴ , (b) -SO ₃ R ⁵ , (c) -NHSO ₂ CH ₃ , (d) -PO (OR ⁵ ) ₂ , (e) -SO ₂ -NH-R ⁹ , (f) -CONHOR ⁵ ,

(i) -SO ₂ NH-heteroali as defined below, (j) -CH ₂ SO ₂ NH-heteroaryl as defined below, k) -SO ₂ NH-CO-R ²³ , (l) -CH ₂ SO ₂ NH-CO-R ²³ , (m) -CONH-SO ₂ R ²³ , (n) -CH ₂ CONH-SO ₂ R ²³ , (o) -NHSO ₂ NHCO-R ²³ , (p) -NHCONHSO ₂ -R ^23,

(t) -CONHNHSO ₂ CF ₃ , (u) -SO ₂ NH-CN,

(x) -PO (OR ⁵ ) (OR ⁴ ) or (y) -SO ₂ NHCONR ⁴ R ²³ wherein heteroali contains or does not contain 1 to 3 heteroatoms selected from the group consisting of O, N and S Unsubstituted or unsubstituted, mono- or di-substituted 5- or 6-membered aromatic rings, wherein the substituents are -OH, -SH, -C ₁ -C ₄ -alkyl, -C ₁ -C ₄ -alkoxy, -CF ₃ , halo (Cl, Br, F, I), -NO ₂ , -CO ₂ H, -CO _2- (C ₁ -C ₄ -alkyl), -NH _2- , NH (C ₁ -C ₄ -alkyl ) And -N (C ₁ -C ₄ -alkyl) ₂ ); and R ^2a and R ^2b are each independently (a) H, (b) halogen (Cl, Br, I , F), (c) NO ₂ , (d) NH ₂ , (e) C ₁ -C ₄ -alkylamino, (f) di (C ₁ -C ₄ -alkyl) amino, (g) SO ₂ NHR ⁹ , (h) CF ₃ , (i) C ₁ -C ₆ -alkyl, (j) C ₁ -C ₆ -alkoxy, (k) C ₁ -C ₆ -alkyl-S-, (l) C ₂ -C ₆ -alkenyl, (m) C ₂ -C ₆ -alkynyl, (n) aryl as defined below, (o) aryl (C ₁ -C ₄ -alkyl) or (p) C ₃ -C ₇ -cyclo Alkyl, R ^3a is (a) H, (b) halo (Cl, BR, I, F), (c) C ₁ -C ₆ -alkyl, (d) C ₁ -C ₆ -alkoxy or (e) C ₁ -C ₆ -alkoxyalkyl, R ^3b is (a) H, (b) halo (Cl, Br, I, F), (c) NO _2, (d) C ₁ -C ₆ -alkyl, (e) C ₁ -C ₆ -acyloxy , (f) C ₃ -C ₇ -cycloalkyl, (g) C ₁ -C ₆ -alkoxy, (h) -NHSO ₂ R ⁴ , (i) hydroxy (C ₁ -C ₄ -alkyl), (j ) Aryl (C ₁ -C ₄ -alkyl), (k) C ₁ -C ₄ -alkylthio, (l) C ₁ -C ₄ -alkyl sulfinyl, (m) C ₁ -C ₄ -alkyl sulfonyl, (n) NH ₂ , (o) C ₁ -C ₄ -alkylamino, (p) di (C ₁ -C ₄ -alkyl) amino, (q) fluoro-C ₁ -C ₄ -alkyl-, (r ) -SO ₂ -NHR ⁹ , (s) aryl, (t) furyl, (u) CF ₃ , (v) C ₂ -C ₆ -alkenyl or (w) C ₂ -C ₆ -alky Nyl [where aryl is unsubstituted or halo (Cl, Br, I, F), N (R ⁴ ) _2, CO ₂ R ⁴ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, NO _{2 , CF 3, C 1 -C 4} - alkylthio, and is a phenyl or naphthyl group substituted with one or two substituents selected medieval stand consisting of OH], and, R ⁴ is H or above Or by aryl, and it is optionally substituted with a linear or branched C ₁ -C ₆ alkyl substituted by aryl as defined above, R ^4a is as defined above, or notify, substituted aryl is optionally substituted as defined above, straight or branched C ₁ -C ₆ - Alkyl and R ⁵ is H or

E is a single bond, -NR ¹³ (CH ₂ ) _S- , -S (O) x (CH ₂ ) _S- (where x is 0 to 2 and s is 0 to 5), -CH ( OH)-, -O- or CO-, R ⁶ is (a) unsubstituted or halo (Cl, Br, I, F), -OC ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyl,- NO ₂ , -CF ₃ , -SO ₂ NR ⁹ R ¹⁰ , -SC ₁ -C ₄ -alkyl, OH-, NH ₂ , C ₃ -C ₇ -cycloalkyl and C ₃ -C ₁₀ -alkenyl Aryl as defined above substituted with one or two substituents selected from (b) unsubstituted or aryl as defined above, C ₃ -C ₇ -cycloalkyl, halo (Cl, Br, I, F), -OR ⁴ , CF ₃ , CF ₂ CF ₃ -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , -NH-SO ₂ R ⁴ , -COOR ₄ and -SO ₂ Straight or branched C ₁ -C ₆ -alkyl, C ₂ -C ₅ -alkenyl or C ₂ -C ₅ -alkynyl, which may be substituted with a substituent selected from the group consisting of NHR ₉ , (c) N, O and S May contain 1 or 2 elements selected from the group consisting of Mono- or di-substituted heteroaromatic 5 or 6 membered cyclic rings wherein the substituents are -OH, -SH, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, -CF ₃ , halo (Cl, Br, I, F) and NO ₂ ; (d) C ₃ -C ₇ -cycloalkyl, (e) perfluoro-C ₁ -C ₄ -alkyl or (f) H, and R ^7a and R ^7b are independently (a) H, (b) straight chain Or branched C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, or C ₂ -C ₆ -alkynyl, (c) halo (Cl, Br, I, F) or (d) CF _3, or (e) when R ^7a and R ^7b are bonded to adjacent carbon atoms, they may be joined to form a phenyl ring, and R ^8a and R ^8b are independently (a) H, (b) unsubstituted or —OH, -Guanidino, C ₁ -C ₄ -alkoxy, -N (R ⁴ ) ₂ , COOR ⁴ , -CON (R ⁴ ) ₂ , -O-COR ⁴ , -aryl, -heteroaryl, -S (O) xR ²³ , -tetrazol-5-yl-CONHSO ₂ R ²³ , -SO ₂ NH-heteroaryl, -SO ₂ NHCOR ²³ , -PO (OR ⁴ ) ₂ , -PO (OR ⁴ ) ₂ , -PO (OR ⁴ ) C ₁ -C ₆ -alkyl substituted with a substituent selected from the group consisting of R ₉ , -SO ₂ NH-CN and -NR ¹⁰ COOR ²³ , (c) -COaryl, (d) -C ₃ -C ₇ -Cycloalkyl, (e) -halo (Cl, Br, I, F), (f) -OH, (g) -OR ²³ , (h) -C ₁ -C ₄ -perfluoroalkyl, (i) -S (O) xR ²³ , (j) -COOR ⁴ , (k) -S O ₃ H, (l) -NR ⁴ R ²³ , (m) -NR ⁴ COR ²³ , (n) -NR ⁴ COOR ²³ , (o) -SO ₂ NR ⁹ R ¹⁰ , (p) -NO ₂ , ( q) -N (R ⁴ ) SO ₂ R ²³ , (r) -NR ⁴ CONR ⁴ R ²³ ,

(t) -aryl or -heteroaryl as defined above, (u) -NHSO ₂ CF ₃ , (v) -SO ₂ NH-heteroallyl, (w) -SO ₂ NHCOR ²³ , (x) -CONHSO ₂ R ²³ , (y) -PO (OR ⁴ ) ₂ , (z) -PO (OR ⁴ ) ₂ , (aa) -tetrazol-5-yl, (bb) -CONH (tetrazol-5-yl), (cc) -COR ⁴ , (dd) -SO ² N or (ee)

Wherein n is 0 or 1, R ⁹ is H, C ₁ -C ₅ -alkyl, aryl or arylmethyl, R ¹⁰ is H or C ₁ -C ₄ -alkyl, and R ¹¹ is H , C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkenyl, C ₁ -C ₄ -alkoxyalkyl or

Wherein R ²⁰ is H, —NO ₂ , —NH ₂ , OH or —OCH ₃ , R ¹² is —CN, —NO ₂ or —CO ₂ R ⁴ , and R ¹³ is H, (C ₁ -C ₄ -alkyl) CO-, C ₁ -C ₆ -alkyl, yl, C ₃ -C ₆ -cycloalkyl, aryl or arylmethyl, R ¹⁴ is H, C ₁ -C ₈ -alkyl, C _1- C ₈ -perfluoroalkyl, C ₃ -C ₆ -cycloalkyl, aryl or arylmethyl, R ¹⁵ is H or C ₁ -C ₆ -alkyl, R ¹⁶ is H, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, aryl or arylmethyl, R ¹⁷ is —NR ⁹ R ¹⁰ , —OR ¹⁰ , —NHCONH ₂ , —NHCSNH ₂ ,

or

R ¹⁸ and R ¹⁹ are each independently C ₁ -C ₄ -alkyl, or together they form — (CH ₂ ) q—, where q is 2 or 3, and R ²¹ is H, aryl Or unsubstituted or aryl, -NH ₂ , -NH (C ₁ -C ₄ -alkyl,), -N (C ₁ -C ₄ -alkyl) ₂ , -CO ₂ R ⁴ , -OH, -SO ₃ H, Or C ₁ -C ₄ -alkyl substituted with SO ₂ NH ₂ , R ²² is aryl as defined in (a), (b) heteroaryl as defined above or (c) unsubstituted or aryl as defined above, heteroaryl as defined above, -OH, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , CO ₂ R ⁴ , halo (Cl, Br, F, I) and -CF C ₁ -C ₄ -alkyl substituted with a substituent selected from the group consisting of ₃ , R ²³ is aryl as defined above in (a), heteroallyl as defined above (b), C ₃ -C ₇ -cycloalkyl, ( d) unsubstituted or aryl as defined above, heteroaryl as defined above, -OH, -SH, C ₁ -C ₄ -alkyl, -O (C ₁ -C ₄ -alkyl), -S (C ₁ -C ₄ -alkyl ), -CF _3, A (Cl, Br, F, I ), -NO 2, -CO 2 H, CO 2 -C 1 -C 4 - _{alkyl, -NH 2, -NH (C 1} -C 4 - alkyl) -N (C C ₁ -substituted with a substituent selected from the group consisting of ₁ -C ₄ -alkyl) ₂ , -PO ₃ H ₂ , -PO (OH) (OC ₁ -C ₄ -alkyl) and -PO (OR ⁴ ) R ⁹ . C ₆ -alkyl or (e) perfluoro-C ₁ -C ₄ -alkyl, X is a) carbon-carbon single bond, b) -CO-, c) -O-, d) -S-,

_{h) -OCH 2 -, i)} -CH 2 O-, j) -SCH 2 -, k) -CH 2 S-, l) -NHC (R 9) (R 10), m) -NR 9 SO 2 -, n) -SO ₂ NR ^9- , o) -C (R ⁹ ) (R ¹⁰ ) NH-, p) -CH = CH-, q) -CF = -CF-, r) -CH = CF- , s) -CF-CH-, t) -CH ₂ CH _2- , u) -CF ₂ CF _2- ,

And r is 1 or 2. The compound of claim 1, wherein J is —C, (0) —, and K and L combine together to form an aromatic ring of 6 carbon atoms substituted with R ^7a , R ^7b , R ^8a , and R ^8b , and R ¹ Is (a) -COOH,

(c) -NH-SO ₂ CF ₃ , (d) -SO ₂ NH-heteroaryl as defined in claim 1, (e) -CH ₂ -SO ₂ NH-heteroaryl as defined in claim ₁ , (f)- SO ₂ NH-CO-R ²³ , (g) -CH ₂ SO ₂ NH-CO-R ²³ , (h) -CONH-SO ₂ R ²³ , (i) -CH ₂ CONH-SO ₂ R ²³ , (j ) -NHSO ₂ NHCO-R ²³ or (k) -NHCONHSO ₂ -R ²³ , R ^2a is H, R ^2b is H, F, Cl, CF ₃ , C ₁ -C ₆ -alkyl, C ₂ -C ₄ -alkenyl or C ₂ -C ₄ -alkynyl, R ^3a is H, R ^3b is H, F, Cl, CF ₃ , C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₅ -C ₆ -cycloalkyl, -COOCH ₃ , -COOC ₂ H ₅ , -SO ₂ -CH ₃ , NH ₂ , -N (C ₁ -C ₄ -alkyl) ₂ Or -NH-SO ₂ CH ₃ , E is a single bond, -O- or -S-, R ⁶ is (a) unsubstituted or C ₃ -C ₅ -cycloalkyl, Cl, CF ₃ , -CCl ₃ C ₁ -C ₅ -alkyl substituted with a substituent selected from the group consisting of -O-CH ₃ , -OC ₂ H ₅ , -S-CH ₃ , -SC ₂ H ₅ , phenyl and F, (b) C ₂ -C ₅ -alkenyl or C ₂ -C ₅ -alkynyl or (c) C ₃ -C ₅ -cycloalkyl, R ^7a and R ^7b is each H, and R ^8a and R ^8b are each independently a) H, b) unsubstituted or COOR ⁴ , OCOR ^4a , OH or substituted C ₁ -C ₄ -alkyl, c) C ₂ -C ₄ Alkenyl, d) -OH, e) -NO ₂ ,

g) -C ₁ -C ₄ -alkoxy,

i) -NR ⁴ R ²³ , j) halo (Cl, F, Br), k) -CF ₃ , l) -CO ₂ R ⁴ , m) -CO-aryl as defined in claim 1, n) -S ( O) _x -C ₁ -C ₄ -alkyl, o) -SO ₂ -NH-C ₁ -C ₄ -alkyl, p) -SO ₂ -NH-aryl as defined in claim 1,

r) A compound as defined in claim 1 or s) -NR ⁴ -CONR ⁴ R ^23, wherein X is a CC single bond and r is 1; The compound of claim 1, wherein K is -C (O)-, J and L are linked together to form an aromatic ring of 6 carbon atoms substituted with R ^7a , R ^7b , R ^8a , and R ^8b , wherein R 1 is ( a) -COOH,

(c) -NH-SO ₂ CF ₃ , (d) -SO ₂ NH-heteroaryl as defined in claim 1, (e) -CH ₂ -SO ₂ NH-heteroaryl as defined in claim ₁ , (f)- SO ₂ NH-CO-R ²³ , (g) -CH ₂ SO ₂ NH-CO-R ²³ , (h) -CONH-SO ₂ R ²³ , (i) -CH ₂ CONH-SO ₂ R ²³ , (j ) -NHSO ₂ NHCO-R ²³ or (k) -NHCONHSO ₂ -R ²³ , R ^2a is H, R ^2b is H, Cl, CF ₃ , C ₁ -C ₆ -alkyl, C ₂ -C _4- Alkenyl or C ₂ -C ₄ -alkynyl, R ^3a is H, R ^3b is H, F, Cl, CF ₃ , C ¹ -C ⁶ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₅ -C ₆ -cycloalkyl, -COOCH ₃ , -COOC ₂ H ₅ , -SO ₂ -CH ₃ , NH ₂ , -N (C ₁ -C ₄ -alkyl) ₂ or- NH-SO ₂ CH ₃ , E is a single bond, -O- or -S-, R ⁶ is (a) unsubstituted or methyl, ethyl, Cl, CF ₃ , CCl ₃ , -O-CH ₃ ,- C ₁ -C ₅ -alkyl substituted with a substituent selected from the group consisting of OC ₂ H ₅ , -S-CH ₃ , -SC ₂ H ₅ , phenyl and F, (b) C ₂ -C ₅ -alkenyl or C ₂ -C ₅ -alkynyl or (c) C ₃ -C ₅ -cycloalkyl, R ^7a and R ^7b are each H , R ^8a and R ^8b are each independently a) H, b) C ₁ -C ₄ -alkyl unsubstituted or substituted with COOR ⁴ , OCOR ^4a , OH or aryl, c) C ₂ -C ₄ -alkenyl, d) -OH, e) -NO ₂ ,

g) -C ₁ -C ₄ -alkoxy,

i) -NR ⁴ R ²³ , j) halo (Cl, F, Br), k) -CF ₃ , l) -CO ₂ R ⁴ , m) -CO-aryl as defined in claim 1, n) -S ( O) _x -C ₁ -C ₄ -alkyl, o) -SO ₂ -NH-C ₁ -C ₄ -alkyl, p) -SO ₂ -NH-aryl as defined in claim 1,

r) aryl or s) -NR ⁴ -CONR ⁴ R ²³ as defined in claim ¹ , X is CC single bond or -CO-, r is 1; The compound of claim 1, wherein K is —C (═NR ²² ) —, and J and L are linked together to form an aromatic ring of 6 carbon atoms substituted with R ^7a , R ^7b , R ^8a , and R ^8b , wherein R ¹ is (a) -COOH,

(c) -NH-SO ₂ CF ₃ , (d) -SO ₂ NH-heteroaryl as defined in claim 1, (e) -CH ₂ SO ₂ NH-heteroaryl as defined in claim 1, (f) -SO ₂ NH-CO-R ²³ , (g) -CH ₂ SO ₂ NH-CO-R ²³ , (h) -CONH-SO ₂ R ²³ , (i) -CH ₂ CONH-SO ₂ R ²³ , (j) NHSO ₂ NHCO-R ²³ or (k) NHCONHSO ₂ -R ²³ , R ^2a is H, R ^2b is H, F, Cl, CF ₃ , C ₁ -C ₄ -alkyl, C ₂ -C ₄ -al Kenyl or C ₂ -C ₄ -alkynyl, R ^3a is H, R ^3b is H, F, Cl, CF ₃ , C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C _2- C ₄ -alkynyl, C ₅ -C ₆ -cycloalkyl, -COOCH ₃ , -COOC ₂ H ₅ , -SO ₂ -CH ₃ , NH ₂ , -N (C ₁ -C ₄ -alkyl) ₂ or -NH -SO ₂ CH ₃ , E is a single bond, -O- or -S-, R ⁶ is (a) unsubstituted or C ₃ -C ₅ -cycloalkyl, Cl, CF ₃ , CCl ₃ , -O- C ₁ -C ₅ -alkyl substituted with a substituent selected from the group consisting of CH ₃ , -OC ₂ H ₅ , -S-CH ₃ , -SC ₂ H ₅ , phenyl and F, (b) C ₂ -C _5- Alkenyl or C ₂ -C ₅ -alkynyl or (c) C ₃ -C ₅ -cycloalkyl, R ^7a and R ^{When 7b} is each H or R ^7a and R ^7b are bonded to adjacent carbon atoms, they can be linked to form a phenyl ring, and R ^8a and R ^8b are independently (a) H, (b) unsubstituted or COOR ⁴ , OCOR ^4a , C ₁ -C ₄ -alkyl substituted with OH or ali, (c) C ₂ -C ₄ -alkenyl, (d) -OH, (e) -NO ₂ ,

(g) -C ₁ -C ₄ -alkoxy,

(i) -NR ⁴ R ²³ , (j) halo (Cl, F, Br), (k) -CF ₃ , (l) -CO ₂ R ⁴ , (m) -CO-aryl as defined in claim 1, (n) -S (O) xC ₁ -C ₄ -alkyl, (o) -SO ₂ -NH-C ₁ -C ₄ -alkyl, (p) -SO ² -NH-aryl as defined in claim 1,

(r) A compound as defined in claim 1 or (s) -NR ⁴ -CONR ⁴ R ^23, wherein X is a single bond and r is 1;